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Journal Review in Colorectal Surgery: Total Neoadjuvant Therapy in Rectal Cancer · Behind The Knife: The Surgery Podcast

• Journal Review Total Neoadjuvant Therapy in Rectal Cancer === [00:00:00] Hello to our Behind the Knife listeners. I'm welcoming back the colorectal oncology surgery team, including myself, Winnie Ombre, Phil Bauer, and Dr. Jay Joshua Smith. Today we have an outstanding panel of guests joining us, Dr. Garcia Aguilar, who is the Beno C Schmidt Chair in surgical oncology, the Chief of colorectal service in the Department of Surgery at MSK, the Director of Colorectal Cancer Research Center at MSK, and the professor of Surgery at Weill Cornell Medical College. We also have Dr. Benjamin Schlechter, senior physician in the gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, assistant Professor of Medicine at Harvard Medical School. Also joining us, we have Dr. Emmanuel Fo. Professor and chairman at the Department of Radiation [00:01:00] Oncology, part of the CyberKnife and Radiotherapy Faculty of Medicine at the University Hospital of Cologne in Germany. We appreciate you all taking the time to discuss our topic today. Total new adjuvant therapy in locally advanced rectal cancer. Winnie, can you please provide us some background? Of course, Janet. Locally advanced rectal cancer includes CT three that is tumor invading through the muscularis propria into the subserosa and CT four tumors. That is tumors that has penetrated the outer layers or COSA invading at adjacent organs or structures or tumors involving local regional lymph nodes. In addition to any T stage with node positive disease, it should be noted that CT three N zero M zero tumors also fall into this category. NCCN guidelines recommend toll neoadjuvant therapy as a current standard of care for all [00:02:00] non-metastatic locally advanced disease. But this varies slightly from European recommendations. According to ESMO guidelines, TNT should be considered for high risk tumors in the surgical setting, and these are defined as clinical T four tumors. Those with concern from meso rectal fascia involvement clinical node N two tumors positive extramural vascular invasion or EMVI or lateral lymph node enlargement of greater than or equal to seven millimeters in the organ preservation setting. The ESMO guidelines for TNT are the same as the Oprah trial, which we'll discuss shortly. With that background, Dr. SCH selector, could you please provide us a history of TNT and, and which studies laid the groundwork for these recommendations? Yeah, happy to. So, I think we have a pre TME era and a TME era, and so the TME era. Really changed practice. So first we have the Swedish rectal the Swedish Rectal Cancer Trial, which looked at short course radiation followed by surgery. But this is a trial in which surgery was not standardized, and nead radiation did improve local control [00:03:00] and overall survival. Subsequently, we had the Dutch trial, which address addressed the same question of neoadjuvant radiation, but standardized TME across all institutions. And this was led by DR. Held. So the local recurrence rates were improved in both arms, and there was still an improvement in local control in patients that received neoadjuvant radiation even when TME was optimized, although overall survival. Benefit was was less. So in 2004 there was the A IO 94, the German Rectal Cancer Trial group, but demonstrated pre preoperative chemoradiation reduced the rates of local recurrence and acute and long-term toxic effects. The American N-S-A-B-P-R-O four RO three rather trial had similar results, but treatment compliance was improved and there was increased sphincter preservation, which obviously is important for patients. So neoadjuvant chemoradiation followed by TME plus or minus adjuvant therapy was adopted as standard of care worldwide. And by 2014, we had the endorse trial coming outta the uk, which really standardized FOLFOX as the adjuvant [00:04:00] chemotherapy. You know, this strategy offered good local control, but there were some important lessons. So first, a significant portion of patients never received the intended post-op chemotherapy. Often because they were still recovering from surgery, they had complications, and there's just delays in treatment. And as a result, this really allows micrometastatic disease to progress. Unchecked during this long interval, and we wanna obviously avoid micrometastatic disease. A medical oncologist metastatic disease is sort of my business. And so there was reasons to think that we could fill the space in the neoadjuvant setting with, with the chemotherapy that was offered adjuvant based on the door trial. So at this same time, the interval between radiation and surgery was being evaluated and the Stockholm three trial looked at short course radiation with a delayed to surgery or short course radiation with immediate surgery. And this showed that a delayed to surgery led to a tenfold increase in pathologic complete response. So that's really impressive. This also highlighted the time, the, the value of time for regression, [00:05:00] but concerns persisted about delaying surgery and avoiding systemic therapy. And so some timing trials and four successive trials looked at progressively longer radiation to surgery intervals and filling that time with modified FOLFOX or KO. The rate of pathologic complete response essentially doubled with these trials from 18 to 38%, supporting the idea that additional time between radiation and surgery can enhance tumor response, and that we can prolong disease free survival and potentially allow non-operative management, but importantly also get in the chemo that we oncologists like to get in. So by shifting systemic therapy and radiation therapy into the pre-op period, patients are more likely to get all of the intended therapy. We're more likely to address micrometastatic disease with chemotherapy, and we're more likely to essentially achieve benefits for patients including complete responses. Ultimately, TNT in this era, the sort of the later part of the TME era, I would say is the TNT era is associated with [00:06:00] higher rates of path cr, which opens the door for organ preservation, things that patients and surgeons really, really want, and opens the door for non-operative management watch and wait strategies, and in some cases improves the chance of sphincter preservation for lower tumors. Thank you Dr. Lecter for that nice overview. It should be noted that some recent studies have I aimed to identify the optimal type of radiation dosing, even chemotherapy regimens to be used, and then the sequencing of treatment based on some of what you just discussed, including the timing trial. So two examples are the RAPIDO study and the Prase 23 trials, both randomized trials that were two landmark studies incorporating this idea of to neoadjuvant therapy that certainly deserved further review. Both showed higher rates of pathologic complete response when using a total neoadjuvant approach and improvement of the oncologic outcomes measured in both of the studies. [00:07:00] Rapido was interesting because it used a short course radiation approach followed by four months of either FOLFOX or KPO versus just the standard long course chemoradiation. Followed by TME surgery and then adjuvant therapy. The five-year outcomes showed that short course TNT doubled the path CR rates compared to long course chemo radiation and showed improved oncologic outcomes as measured in the trial. However, and notably, long-term data revealed a higher local regional failure rate in this trial. And this led to the question the the use of short course radiation in this context in the Perdu 23 trial, which utilized folfirinox, and this was six cycles followed by long course chemoradiation compared to the standard approach at the time long course chemoradiation followed by TE surgery and then adjuvant chemotherapy even at the early time point of three years. And that five years, and then impressively at seven years, all of the oncologic outcomes were improved [00:08:00] Using this triplet TNT approach with improvement in disease-free survival, overall survival, and testis free survival. The experimental arm, which was the use of FOLFIRINOX or triplet chemotherapy. So these studies confirmed the safety and efficacy of TNT by demonstrating improved tumor down staging, reduced distant recurrence and better oncologic outcomes including disease three, survival as noted in the produced 23 study. And this ushered in the idea that TNT was safe, efficacious, and improved oncologic outcomes, and also brought in the idea that it would become a standard of care prior to TME for patients with locally anal cancer. Thanks Dr. Smith. So alongside the rise of TNT interest also grew in non-operative management for patients achieving a clinical complete response. And the first group to implement a selective non-operative approach with such patients with a clinical complete response [00:09:00] was Dr. Haber Gamma's group in 2004. Retrospectively they compared the outcomes of 71 patients who were observed without surgery after achieving a clinical CR with the outcome of patients. Who achieved a past CR after TME, their results mirrored a past CR rates of 25 to 30% seen in other studies, particularly when using an extended chemoradiation regimen of 54 gray compared to what would we consider the standard of 50.4 gray in patients early stage low rectal tumors. In that initial study, the overall survival and disease-free survival rates of five years were 100% and 92% respectively in the non-operative group compared to 88 and 83% respectively in the resected group. So this study paved the way for future research into organ preservation in locally advanced rectal cancer. Now, this study was infamously, met with skepticism, but gained traction over time. And [00:10:00] the principles used by Dr. Hobar Gamma's team to assess for clinical CR and monitor for regrowth were adapted to TNT surveillance strategies we used today. This is a great segue into the case that we'll be discussing today. We have a healthy 54-year-old male diagnosed with an MMR proficient T three N one M zero rectal adenocarcinoma. He's coming in to discuss treatment options. His tumor sits at six centimeters from the anal verge. He has never had surgery before and is otherwise healthy with no significant past medical history. He has heard of watch and wait or the non-operative management route and wants more information. To answer this question, we'll be discussing Dr. Garcia Aguilar's, organ preservation in patients with a rectal adenocarcinoma treated with total neoadjuvant therapy, an article published in the Journal of Clinical Oncology in 2022. Dr. Garcia Aguilar, can you please provide us with a summary [00:11:00] of of the Oprah trial and key takeaways? Thank you Janet. Yeah, we'll discuss the design of the opera trial. Let me start by saying that designing a prospective trial in organ preservation is difficult because of the need to randomize patient to very different treatments surgery with no surgery. So for the opera trial, we designed a large phase two study in which patients treated with total vaginal therapy were offered watch and wait, or TME based on clinical complete response assessed by endoscopy and MRI, approximately eight weeks after the end of total therapy. The study primary endpoint was the disease-free survival. The hypothesis was that a treatment strategy that will offer what and way to patient with a clinical computer response will result, will result in equivalent survival compared to historical controls, patients treated with chemo radiation, TME surgery and postoperative adjuvant chemotherapy. [00:12:00] The study offered the possibility of randomizing patients to the two types of total neoadjuvant therapy that has been described before, a chemoradiation followed by systemic chemotherapy versus systemic chemotherapy, followed by chemoradiation. And that was a secondary endpoint to compare the organ preservation with those different ME strategies. What we have learned from the trial is that approximately 50% of patients achieve sustained clinical complete response organ preservation. The response rate was slightly higher among patients treated with chemoradiation, followed by systemic chemotherapy compared to patients treated with chemotherapy, followed by chemoradiation. Survival rates were equivalent to patients treated with the standard treatment of chemo radiation, TME, surgery and postoperative vaginal chemotherapy. And we didn't find any differences in disease-free survival, overall survival, local recurrence of metastasis between the two treatment arms. Of the study, [00:13:00] we learned that most patients offer, watch and wait went to have a sustained clinical complete response, but there was a number of them that developed regrowth during surveillance phase, most of the regrowth occur within the first two years from the time of the assessment of response. You know, there was a difference in the response rate depending on the degree of response the study offered. Possibility of entering into the watch and wait strategy for a patient who had complete clinical response based on the fine criteria, but also offer the possibility of a watch and wait to patient with near complete response. Those who, those who didn't have complete healing of the tumor site but they have some characteristics that again, were defined in the base of the study. Patient with their complete response had a greater rate of tumor, but more than half of them still achieve sustained organ preservation. Those are the main findings of the study that they were [00:14:00] observe at three years of follow up and they were confirm with, you know, for the follow up up to five years. Thank you, Dr. Garcia Aguilar. Going back to our clinical case, our patient undergoes TNT and has a near complete response on imaging and endoscopy after Garcia. Aguilar, can you discuss your approach to a patient with a near complete response? Yeah. With the, in the opera trial design, our internet was to give tumor the maximal opportunity to respond. As Dr. Sadler mentioned before, timing of the semial response is essential. Rectal cancer takes time to respond, and we wanted patient who did not have a complete clinical response at the time of restaging, give them the opportunity of further observation to determine whether we, that partial response will turn into a complete response. That's the reason why we offer patient with near complete response the possibility of inter watch and weight. As I mentioned before, half of them still develop a sustained [00:15:00] clinical complete response. The question is whether for patient who do not achieve a clinical complete response, we put them at risk of tumor progression during the additional observation, and, and that emphasized the importance of, of pretty close clinical surveillance during watch and wait. Thank you so much. Next, Dr. Focus, I'd like to hear your thoughts on how we can treat our patient case. It would help for us to first discuss some of your work on the C-A-O-A-R-O-A-I-O 1216 and 18 trials. Yes, thank you for the kind invitation. When it comes to management of patients with mere CCR, one of the aspects you need to consider is the duration of TNT. So I don't think we can put all TNT trials into one basket considering the different duration of treatment. And what was very impressive regarding the opera trial of Julio Garcia Glar was the fact that for the first time. [00:16:00] They waited for 34 weeks. That is eight and a half months after treatment initiation, before assessing tumor response and deciding whether patients will be opted for what and wait in case of CCR, near CCR or tumor surgery in case of poor response. And this is a key detail that has been ignored for a long time, but we always need to keep it in the, in, in our mind because the vast majority of, of TNT trials were characterized by different duration in our center. Now, outside clinical trials, we recommend a watch and wait if the patient is happy with our recommendation. But at the same time, we present the case at the MDT and we trying to to organize a consultation with the surgical department 'cause important to us that the patient also hears the opinion and the point of view of the surgeons. And now to the 12th [00:17:00] trial. And this abbreviation reflects the three oncological societies of the German oncology community. That's the surgical, the in medical oncology, and the radiation oncology. Like the opera. It was a randomized phase two study and randomized TNT with either induction or consolidation chemotherapy with less chemo. However, the chemo radiotherapy part had a more intensified, concomitant chemotherapy protocol that is not only fluorine, but five FG oxaliplatin. So the cumulative dose of oxaliplatin for those interested was 500 milligrams which corresponds to the. Total dose if you prescribe adjuvant chemotherapy for three months in colon cancer. The primary endpoint was PCR. What we showed is that the consolidation chemotherapy resulted in superior PCR rates. That was 25% [00:18:00] compared to induction chemotherapy. That was 17%. Few patients rejected surgery al by the clinical design, indicate that TME was compulsory. So the cumulative pcr, ccr H were. 28% for the consolidation chemotherapy arm and 21 for the induction. Why we did this trial, this was a pick the winner design. The reason why we did that is was because we wanted to to choose the best TMT ARM to test the efficacy for organ preservation in the next generation trial. That was the 16 D 18. Before I proceed to the 16 trial of the chairman group, I want to mention that the long-term analysis indicated that there was no difference between the two groups regarding the other secondary oncological endpoints, anorectal function, and toxicity. Now, the 16 was led [00:19:00] by Ian Gani from the University of two begin. For that, we chose the group B of the 12 trial. That is chemotherapy first, followed by consolidation chemotherapy with three cycles of ox and. Similar to the opera, we performed analysis of response at two different time points in case of the pace in case of patients with a very good or near CCR. Now this trial indicated CCRH of 40% surprisingly, the, despite the trial design, many patients were operated. The PCR eight in this trial was 28%. This reflects, I think, uncertainty of some of the centers during the first period before they became familiar with assessing response as part of the watch and wait program. Since then, we have moved forward. Very important though, and this is the reason why we advocate, [00:20:00] watch, and wait, but the TME group. Was characterized by significantly, significantly worse, anorectal urogenital function, and of course quality of life compared to the subgroup of patients that were opted for. Watch and wait be because of CCR. And this is, this is the reason why we do advocate, watch and wait. There is no other reason now. Following the completion of the 16, we're very happy that to see the C, c and PCRH. Why? Because at the same time, or shortly afterwards, we initiated the 18.1. It was a large randomized phase three study and compared, tNT per rapid, that is five times five, followed by Capox or FOLFOX over a period of 16 to 18 weeks. And in group B was the continuation or further development of R 12 and 16 trial concept that is chemo radiotherapy. First intensified, concomitant chemo [00:21:00] protocol with five FG oxaliplatin, followed by either six cycles of FOLFOX or four cycles of cap O. So we did this trial following publication or presentation of the, of the rapido because the rapido indicated an improvement in one of the key oncological endpoints that was DFS. The hypothesis is that that chemo radiotherapy based TNT will lead to an improvement in the three year organ preservation rate. The primary endpoint from 30% per API O to 40% according to our group with the chemotherapy trial complete accrual in September 23 with 702 patients. And this is the first trial that we, I have seen personally that completed accrual two years before initial projection of the projected time. Why? The reason was, of course, the very good multidisciplinary teamwork the support from the German cancer aid that has been [00:22:00] funding our trial. But I think the most important reason is because patients with rectal cancer, especially of the lower third, do want to be treated as part of studies that assess and test the concept of organ preservation. This is definitely a, a paradigm changing era and we're very excited to complete this trial and we very much hope to be able to present to you and the community the data early next year now. Last point I want to touch upon was the slight controversy that we have all experienced during the last period regarding whether it's safe to advocate organ preservation. There has been some skepticism, especially regarding the outcome of patients with near CCRI think. I think the data are excellent when it comes to CCR. You have a DFS Os over 90%, and of course we have the other extreme that is poor response. In this case, you [00:23:00] definitely need to operate, but for patients with near CCR, you, you always wonder if I, if I actually advocate a restaging three months. Will this lead to a worsening of the oncological endpoint? So with this in mind, the German group and the opera group with Professor Aguilar and Professor Smith decided to conduct a pooled analysis that we published early this year. There was a pool analysis of the 12 trial of the German group and the opera. I think this is the best evidence to compare the clinical outcome between two randomized TNT studies that randomized or se or tested the two different TNT sequences. And I encourage the community to read the paper because we could, we could show that for the different response groups based on clinical and pathological response assessment, the DF, S and OS were completely, completely comparable. So in patients with. You know, there was no difference in the [00:24:00] outcome between patients that had a near CCR assessed clinically, and patients that had intermediate pathological response according to the vRAC system established since 25, 30 years ago by the chairman group. But I'm sure professor Aguilar would like to add to it. Thank you, professor Foca. Not much to add. I think as I mentioned before, the design of the opera trial was in reality, a single arm in which patients with response, complete response to total measure therapy will be offered. What and weight, or TME based on their response, we initially power the study based on historical controls, and I think the study that has been later published by Professor Focus and his group from Germany is because of the design. With similar, similar, not, not exactly the same, but similar TNT strategies represents the be control arm. So in the absence of a prospective randomized trial, probably this is the strongest evidence in support of a treatment strategy for locally advanced breast cancer that [00:25:00] offered watch and wait to patient with a complete response. And I agree, it's a paper that should be read because the grade of response assessed by endoscopy and MRI after the TNT is an excellent predictor of long-term outcomes. And this is validated with a pathology grading that was performed in the German trial. So, it's, it's again, probably the best validation that we have for the was and greater strategy. Thank you, Dr. Focus and Dr. Garcia Aguilar, it seems like we all have some reading to do. So for our case of a 54-year-old male with locally advanced rectal cancer, what treatment options would you offer the patient from our clinical case based on the evidence we have today? Dr. Schluter, I'm, I'm interested in your thoughts given the data from the medical oncology standpoint. Where do you, where do you start as you discuss these data with your patients? Yeah, so the first thing I would say about the whole picture of modern rectal cancer therapy is I think it's really impressive [00:26:00] that the surgeons have driven the dialogue and the research on doing less surgery than doing non-operative management. Whereas very often I think in the metal oncology world, we have a more, chemo is more better. And I think an example of that is the Purdue 23 where more chemo was really the thing being studied. I think patients have to have a voice here. So for a lower rectal cancer, that's node positive. For patients interested in non-operative management or function, I would tend to advocate for the Oprah approach. You know, chemo radiotherapy followed by chemotherapy. Getting as much time from radiation to consideration of surgery as possible, getting the most bang for your buck from the time effect of chemo radiotherapy, getting in all of your chemotherapy and hoping for non-operative management for patients where the tumor is higher for patients where radiation is a concern, where patient, where patients where an ostomies is less of an issue. I think we can also think about deescalating therapy once again, rather than deescalating away from surgery, which has been the whole sort of TNT and [00:27:00] opportunistic non-operative management dialogue. But thinking about TNT approaches or perioperative approaches that avoid radiation. And that would be the prospect trial where patients who had a T three, T two N one cancer who had no risk of. Sphincter preservation who, who would undergo serv surgeries? LAR could receive chemotherapy only and if they have a good response, avoid radiation entirely. And those patients had good functional outcomes. But I think for a tumor quite this low, I would tend to recommend the Oprah approach over the prospect approach of avoiding radiation deescalating. There are those who would argue strongly that FOLFIRINOX based in produce 23 is the, is the way to go because of that DFS benefit that we see in os benefit in long-term follow-up. I would just make the nuance point that the control arm in that trial was a little bit undertreated and so I don't know that, that I would take a T three N one cancer and escalate all the way to a toxic regimen like folfirinox. Until we have the results of your trial, [00:28:00] the modern Janus trial, looking at FOLFIRINOX in this setting and really in a randomized setting looking at escalated chemotherapy versus standard chemotherapy, FOLFIRINOX versus folfox, really proving the benefit in, in a well-controlled study. And of course we also have a IO studies doing the same thing. And so I think it comes up, comes up to what the patient wants, but I would tend towards an Oprah approach in this particular situation. That's great. Dr. Focus from the European standpoint, do you think in the absence of data from your current phase three trial, do you see a trend toward a more TNT type approach given the OPA data? Or are you still are waiting for the data from your trial, for example, in the management of this patient? Yes. Thank you so, so much for the question. It's a key question because following the publication of the five year data on the RAPIDO trial that indicated worse rates of local regional failure [00:29:00] in the TNT group with five times five, the, at least in Germany, the surgical community. Has become very reserved in advocating TNT with Sarco radiotherapy, even though we as radiation colleagues are the first one who say that, you know, it's important to wait for the phase three data of our 18.1 trial. Nevertheless, we have already experienced a CD nationally towards TNT with chemotherapy. I think following the initial enthusiasm of the first two years upon presentation of therapy, the ASCO 2020, the community has reconsidered its options. And I think it's a valid point because 10% local failure is, is a, is an unacceptable unacceptably high rate. We still don't understand why this happened and this very concerning considering that this occurred in a country with [00:30:00] excellent. Excellent health system that is the Netherlands with centralized health system with very high quality surgical oncology standards. So I'm wondering if that happen in the Netherlands, how the outcome looks in countries with less centralized health system with less subspecialization and less high volume centers. So at the moment, nationally, and I think in Europe most most centers prefer TNT with long core chemo radiotherapy. That's, that's very helpful. And Dr. Garcia Aguilar, what do you think currently in the us what do you think the trend is in the absence of the data from Dr. Focus trial, from our recently completed Janus trial, the Japanese trial? How do you think this patient is being managed from your perspective? I think I, I agree with what have been said, but then, and by manano this patient after a discussion outlining what the goals of the treatment are, if the patient is [00:31:00] interested in ular preservation, he will probably be treated with chemo radiation followed by consolidation chemotherapy. Again, we're waiting for the results of the phase three trial from Germany, but I think for the most part in United States, the standard now would be chemoradiation followed by chemotherapy. If the goal is on preservation. The one point I would add, actually, would be how symptomatic he is. You know, one of the important findings from Purdue 23, I thought was the analysis that for the most symptomatic patients, starting with chemotherapy, led to symptomatic improvement more quickly. Again if his organ function right now was pretty good, he wasn't really suffering that much, I would definitely. Recommend an Oprah approach, but if sometimes you have a rectal cancer, you know, at six centimeters, it's pretty miserable. And for those patients, they do get better quickly with folfirinox. And I think that's the one situation where, unless the patient is adamantly opposed to an the risk of an ostomy, I would I would pretend to offer FOLFIRINOX in that particular situation, which is a little bit beyond the randomized data. But I do think it's, it's worth [00:32:00] considering. 'cause ultimately we're not changing overall survival in most of these approaches, and it's really about function and quality of life. And so using chemotherapy to improve quality of life is a consideration in this situation. Although I think in this particular patient, Oprah's the way to go. Yeah, I think I tend to agree that's a, that's a very good point because at the end of the day, the difference in organ preservation between the induction and consolidation arm is not a huge, it's still close to 40% of the patient who start with systemic chemotherapy can achieve organ preservation. So I think that is a very, a very good point and well taken. Yeah, it is a good point. Dr. Foco, I wonder if you could comment just on. Timing to get mediation started and also the improvement of symptoms from, from your perspective. So nationally and in Europe we had endless conversations for almost two and a half years. How to update the clinical guidelines and again, for those interested, I encourage you to read the esmo, they look pretty similar to the national German or the German look pretty national, pretty similar to the esmo. [00:33:00] To cut a long story short, we have two different clinical settings. So we have two separate algorithms for the two fundamental different clinical settings. The first one is the surgical, and the second one is the setting of organ preservation and hard as it is. You need to decide at the beginning, of course, as part of the third decision making with your patient and upon presentation of the case at the MDT, whether the aim of the treatment is organ preservation or not, if there is, if the aim is organ preservation, we have no data on the role of induction chemotherapy. However, we have trials ongoing on chemo and we look forward to them. In fact, there is a trial completed in France for patients with intermediate risk that compared FOLFIRINOX versus chemo radiotherapy and of, but if the, if the aim is surgery, of course you can start with chemotherapy, especially for those PA patients. If that's the recommendation [00:34:00] of the MDT, it's a valuable and absolute valid option. Thank you all so much for those insights. It sounds like there is definitely ongoing research and total adjuvant therapy that we have to stay tuned in with including the role of immunotherapy. During our, our last podcast, we had an in-depth discussion with Dr. Sik and Dr. Yu about early onset colorectal cancer, including the role of immunotherapy for mm r deficient rectal cancer patients. But what about MSS tumors? Dr. Schlechter, are you able to give us information on the role of immunotherapy and MSS s colorectal cancer patients? I'm happy to. The first thing I would say is mature data is lacking, so everything I'm gonna talk about is aspirational oncology as opposed to established oncology. Last year in nature medicine I and Dr. Bullock published on a regimen combination called [00:35:00] Umab with umab. Umab is a next generation CTLA four inhibitor, and it really is a differentiated drug after the Tremelimumab Ipilimumab of the world. This is kind of the the next CTLA four, and it does some different things. It improves clearance of regulatory T cells. It improves activation of the immune system and results in responses. We believe in a large phase one trial and a presented phase two randomized trial in advanced colorectal cancer. So that's important. And importantly, we don't see responses in the liver. We see 'em outside of the liver, and there's a lot of nuance there we can discuss in another setting. There have been three clinical trials looking at umab with umab. In colon cancer, not really rectal cancer, but colon cancer. In the neoadjuvant setting, there's the Nest one and Nest two trial, and then there's the unicorn study that coming outta the goner group in nest One and Nest two, or from New York. What they showed was that bot Umab followed by baab does improve clinical complete [00:36:00] responses in patients undergoing resection of a colon cancer. It begs the question whether we could use a similar approach in rectal cancer and we're actively applying for funding and investigating this. And this is a really, really important option to think about, but as of now, I would not offer umab, and Umab is neoadjuvant therapy for rectal cancer. But I think it's a really appealing idea because this is a combination with significant responses compared to conventional checkpoint inhibitors. So that's the, the new drug is the Umab Bastil, and I'm sure other companies are gonna start trying to make the. Umab competitors because it's a powerful drug and it's an important drug, and it's entering phase three trial for registration and refractory disease. And hopefully we can get that trial quickly into early stage disease and help patients with rectal cancer using immune therapy approach. There have been two phase twos worth knowing about in total neoadjuvant therapy in combination with PD one inhibitors. So there's the torch study, and that is a short course radiation paradigm. And then every patient received the same amount of KA plus [00:37:00] immune checkpoint inhibitor. I always have trouble pronouncing this one. It's umab. So umab is a PD one similar to nivolumab or pembrolizumab, for example, direct that trial looked at short course radiation, followed by a TNT approach, similar to rapido. Or some amount of chemotherapy, immunotherapy, and then radiation and then additional chemoimmunotherapy. And what it showed was that the radiation first approach was better. I actually think this really was looking at a radiation first versus radiation midway through therapy as opposed to the plus or minus immune therapy. And pretty much every trial we've discussed, the longer you wait from radiation, the better your local control effect is. And so my guess is that torch demonstrates the safety of the combination of short course radiation followed by this PD one inhibitor in KO. But doesn't necessarily say that it's better. It does look good compared to historic controls, but I don't think historic controls are really valid in a curative intent therapy approach. So there was another trial looking at [00:38:00] an immune checkpoint inhibitor, also a PD one called Sentab, and that's. Was combined with KPO, so it was KO followed by chemo radiotherapy, followed by surgery, non-operative management with plus or minus umab and, and that did show a trend toward improvement in non-operative management in those patients. We don't have overall survival data yet, but the important thing about that was that was a really straightforward randomization of plus or minus immune checkpoint inhibitors using kind of what I would describe as the losing arm of Oprah. It was a radiation second, not radiation first approach. And so I think we really do need a radiation first approach followed by chemotherapy plus or minus immune checkpoint inhibitors. There's a couple other points I would make. I could go on for an hour, but I'll try to be fast. Radiation. Radiation followed by chemo and immune therapy is an important question to ask. I think we have to ask what's the right immune therapy. The benefit we're seeing with umab, I think speaks to the role of CTLA four, and most of these trials are using PD one or PD L one [00:39:00] inhibitors, and those are different drugs and they work in different ways. The other important point I would make is that the presence of the NC two nodes and the NC two primary and the NC two pyrus patches and immune system of the rectum may enhance the ability of immune therapy to work. So we have to think about our trial designs and think about the role of neoadjuvant therapy versus adjuvant therapy. I would strongly suggest that neoadjuvant approaches are most important when we're thinking about immune therapy in these so-called colder tumors. We need the training ground of the immune system, which is the lymph nodes. We may have to think about the role of radiation. It could be that the biologically effective dose of short course radiation, which is a little bit less than the biologically effective dose of long course radiotherapy, maybe it's less lympho toxic and maybe a short course. Followed by PD one, which is an easier drug to tolerate will be better than the long course. We have to test all of these questions before they enter prime time. But I think we're entering, we had our pre TME era, we have our TME era. We have our TNT non-operative MA [00:40:00] management era, and hopefully we can enter a post TME era with the combination of chemo radiotherapy or radiation therapy, a long gap filled with chemotherapy and immune therapy and increasing amounts of complete responses to non-operative management. And that's really aspiration, I think, of this generation of clinical trials. Thank you so much for that. Do you see this taking the place of a current treatment modality overall? I hope it can do that with time, right? The best thing that we can achieve with chemotherapy and immune therapy and with and radiation therapy and all these modalities is to avoid some modalities. And I think. Surgery is the modality that we wanna avoid. As I said, this has been work led by surgeons to do less rectal surgery. I don't think we're putting colorectal surgeons outta business in the rectum, but I think if we can get more patients avoiding a PR, more patients avoiding LAR syndrome, that would be beneficial. But we have a real long way to go and I would not underestimate rectal cancer's ability to resist immune therapy. [00:41:00] So I think yes, this is going to be part of the deescalation approaches, but I don't think any of the above approaches are going away. Yeah, I think those are great points and interested to see what Dr. Garcia Aguilar and Dr. Focus think 'cause really important points to hear about trying to turn cold tumors hot in the context of radiation. Dr. Focus and then Dr. Garcia Aguilar. I know this is something you've been thinking about a little bit, so I'd be interested to get your insight. Ben great, great. Overview of what is been, what is known now about immune checkpoint blockade in the rec, cancer and perspective for the future, but the success of the immune checkpoint blockade. So far, the great success have been in a properly selected patients, the one that they have you know, MSI, the high tumor mutation burden based on data from svia and others. The, the proportion of tumors MR proficient that they would be expected to respond to immune is limited. [00:42:00] Have you thought about the idea of using some biomarkers to select the patients that will be exposed to a potentially toxic treatment as the combination that you were describing both bowel. Yeah, with pop bowel, we don't have enough data yet. You know, fewer than a thousand patients have probably received that agent, so there just isn't enough high quality biomarker data in these particular diseases to predict who are the winners and who are the losers. We just have to do the trials, the biomarker data that we do have. There's a number of immune scores for conventional PD ones. Yeah, we can slightly better predict who's a winner and who's a loser in these paradigms. I don't think that that we have found anything, particularly practice changing. PD one, staining PD L one, standing on the tumor doesn't really seem to make a huge difference in predicting outcomes. Probably because so-called cold tumors like rectal cancer, they're pushing back against the immune system in different ways than say, lung cancer and melanoma. And so those scoring systems that we use in those diseases probably just don't apply. Yes. If I may add to the immunotherapy, [00:43:00] so Dr. Sch Selecter mentioned earlier that Sarco radiotherapy as part of TNT for combination with immunotherapy might be the better approach. And so far we have evidence that this might be the case, inconvenient as it might be as. We are still waiting to see the date of the 18.1 trial, but I want to highlight two studies that were presented this year at the Estro Congress. This is the European Radiation Oncology Conference that took place in May. The one is the Prime RT from the Scottish Group, Campbell Roxborough, who combined SAR course and long course based TNT with durvalumab. And this small trial indicated, but the response rates in favor of TNT with SAR course radiotherapy when you combine it with the PD one immune checkpoint inhibitor durvalumab. The second trial I want to highlight is the stellar two [00:44:00] by the Chinese group. So this is the continuation of Stellar one. The substance was umab, if I remember correctly, PD one inhibitor. So they present the phase two data, but bear in mind that the phase three trial recruitment has already been completed and indicated very high, very high response rates when you combine TNT with short course with PD one immune checkpoint inhibition. And this together with the, the other nine studies published on different combination immunotherapy with different immune checkpoint inhibitors indicate that we might have got the biology, at least in part, a bit wrong, and maybe recal cancer is not as a cold humor as we have been thinking. And if it was that cold. And we wouldn't have seen such impressive data. So this theory that it is definitely a very cold tumor, might need a bit of reconsideration. I guess it, you know, we cannot extrapolate the data from colon [00:45:00] cancer to rectal cancer. This is what this data from the first 10 11 trials immunotherapy indicate. But as Dr. Schlechter mentioned, we need longer follow up, more mature data, and of course, phase three trial results. But the, from what we have seen so far, if you combine TNT with immunotherapy, might be better to use short course radiotherapy A and B. We cannot extrapolate the biology of colon cancer to rectal cancer, and maybe rectal cancer is not as called immuno genetically as we thought. Yeah, along with what Dr. Foga was saying, I mean, we have dose on track atomic analysis in rare retinal cancer, and there is a small subset, but significantly higher than the ms I tumor, that they're immune heart based on the expression of genes or the immune signature from being there. So that's maybe in the future, what is the response to that particular subset of rectal tumors now, but, but also you both bring an interesting point [00:46:00] about the issue of the type of radiation and the issue of response and the impact of radiation in the lymphatic microenvironment in the rectal area. We take that question to the extreme. Why not just do focal radiation to the primary and forget about the mear rectum? What about the possibility of using contact radiation with high dose to the primary tumor, trying to spare the mear rectum to the best of our ability? I don't know if you guys had any thought about that or any option for additional trials. This is an excellent point. And in fact, there are three ongoing randomized studies and all three come from China exactly on this question. So this is TMT based approach randomized in the standard arm, the both the primary tumor and the pelvic lymph node areas. That is ilial iliac, iliac internal opterator and presacral Lymph nodes are irradiated per standard protocol, and in the experimental group, instead of irradiated both the primary tumor and the [00:47:00] pelvic lymph node areas, you only radiate the primary tumor. And it will be interesting to see whether this will be associated with high response rates, but we have known this since long time ago that chemo radiotherapy n. Radiotherapy are associated with lympho depletion. Lymphopenia is very common. We have kind of overlooked it for long time because in the vast majority of patients, it's asymptomatic patients. You know, so you take blood, you, you conduct a differential blood value analysis and you see high grade of lymphopenia, and then you ask the patient how you feel. And you see there is no symptoms, no infection signs, so you carry on giving chemotherapy, which is fine. But in the context of immunotherapy, this approach needs reconsideration. And what you mentioned, Julio, is absolute spot on. I think we're gonna see very interesting data in the, in the years to come. Exactly on this point from China there, to my [00:48:00] understanding or knowledge, there is no data either from Europe or from the US on this scientific question. Yeah, it's a great point. And what will Lympho depleting matters, right? We wanna lympho deplete regulatory T cells and mylo derived suppressor cells inside the tumor. We wanna leave some lymph node intact as a training ground. I also think we need better immune therapies. PD one is about taking an established immune response and preventing it from exhausting and failing. I think we also need to think about activating more immune responses. That's really what the concept behind umab is. So we need to be thoughtful about our radiation dosing and designs and fields. We need to be thoughtful about the immune checkpoint inhibitors. We're using, and you know, we've been constrained by enthusiasm for PD L one and PD one inhibitors 'cause they're so safe and easy. But we may have actually missed out on CTLA four and other immune checkpoint pathways where there are important steps in activating the immune response that for a generation we've avoided, we're worried about toxicity, we're better at [00:49:00] toxicity now and with immune therapy. So I think we should try and do better immune therapy in addition to addressing exhausting exhaustion of the immune response. Yeah, these are, these are fantastic points and I hope the behind the knife listeners recognize that we have some gold nuggets coming out of this episode from three really, really brilliant clinicians and scientists. So thank you, each of you for those insights. Dr. Bauer and I are gonna end the, the episode by talking about trials and progress and some next steps. So. As mentioned by Dr. Focus, the ongoing 18.1 trial that's now completed and completed, I think you mentioned anos two years ahead of time. Right. So I think this is instructive to the community that when you have a watch and wait option in a modern rectal cancer trial, that this is really important. And he also mentioned that the idea of reducing toxicity, improving quality of life by having that option is, is critically important. And just as a reminder, that [00:50:00] randomized, essentially theo approach versus what was found to be the the ARM and Oprah that had the highest rate of organ preservation, so short course TNT approach versus a long course TNT approach. And that trial will read out, I think you mentioned earlier, that sometime next year. Yes. So that's, that'll be very instructive and we look forward to seeing the data from that trial. In addition, the trial that's happening in Japan. And I think this is notable because in Japan, prior to starting this, that TNT was not done. And so this is a notable trial because it's using a short course approach followed by triplet chemotherapy versus short course and long course and doublet chemotherapy with a watch and weight approach. And the important thing about these TNT trials, and they've also adopted the three-tiered approach that Dr. Garcia Aguilar mentioned in terms of assessing tumor response, endoscopy exam, MRI. And so we'll have a number of trials which can unify all of these regression criteria in [00:51:00] future, which could also be important if we wanted to do a pooled analysis similar to what Dr. Focus and Dr. Garcia Aguilar did with the the German trial and Oprah trial in future. Then in the US we just completed the Janus Rectal Cancer Trial, which compared Oprah, which is long course, and then doublet chemotherapy as the control arm versus the experimental arm, which is long course followed by triplet chemotherapy. Again, with the idea that selective watch and wait in those patients with a clinical complete response could be integrated in the trial. It was a seamless phase two to phase three trial. This trial also accrued a year and a half ahead of time. The end result was 783 patients accrued in this phase three portion, which was dis disease-free survival. The phase two portion was clinical complete response, and this is an alliance trial that by report is the fastest accruing Alliance trial to date. And so we're excited to see those results, but we'll, we'll need to wait a little while to get their results and we'll report out [00:52:00] CCR and DFS at the same time. The chow trial, which is ongoing in Brazil is very interesting because it's comparing long course and then the capecitabine approach versus long course and folfox, and this is important because it's testing this TNT type approach in Brazil for a, in a prospective trial in South America, which I think is important 'cause it's building on the work that Dr. Garcia Aguilar did in the timing trial, which was mentioned earlier. But instead of mandatory TME, those patients are being offered an option for, for watch and wait. So I'll leave it to Dr. Bauer to help us in the episode. One thing I'm very interested in is we talked a little bit about what modalities we can start to eliminate for select patients. We touched on the prospect trial and the selective use of chemoradiation, but can we expand that to treating these patients non-operatively after, you know, neoadjuvant chemotherapy alone? So that trial showed, you know, nearly a 25% PCR rate in patients treated with just neoadjuvant chemo. You know, [00:53:00] can we selectively watch and wait some of those patients? I think that would be very interesting. We also touched quite a bit on the role of chemo immunotherapy. One thing we didn't really talk about today is the role of circulating tumor DNA and disease surveillance and management, and, you know, how we define the predictive role of CTD NA versus, you know, simply the prognostic features of this assay. Dr. Smith, do you have any more perspective on CTD NA. Yeah, I, I think people know that this is CTD is prognostic. That's not a surprise, but whether or not it's predictive and it's utility, especially in making the decision about whether we would recommend a patient pursue watch and weight or not, is still to be determined. And, you know, we collected plasma and will use this as an exploratory analysis. And, and Janice and I know Manos did the same, and I believe, Julio, you have some analysis in Oprah that could be instructive in this, in this space. So I would say there's, this is an area of active investigation, but are [00:54:00] we ready to make any decisions based on ctdna and rectal cancer? In the absence of data from prospective trials, I would say say no, but be interested to hear what Julio, Ben, and, and Manos think. I think yes we need more data. We are not ready for primetime. Yeah. The ctdna, the at baseline we have found at baseline during treatment, after treatment, can predict outcomes. When it comes to identify patient with response. I'm a little bit more skeptical in patients treated with chemoradiation and systemic chemotherapy. We have to remember that there is eight 10% of patients who, who achieve a clinical complete response and still develop these metastasis. That's all gonna be a confounding factor. That doesn't happen in patients treated with immunotherapy because usually they. Pathological response of the primary tumor, at least in the information that we have for an m Ms K is always associated with a complete eradication of the metastatic disease. So I think in that domain, the CTDNA is gonna be very, very valuable. We need to see what is gonna happen in patients [00:55:00] treated with conventional chemoradiation or systemic chemotherapy when the eradication of metastatic disease is not a hundred percent. That might be a confounding factor at the time of deciding whether the patient is a candidate for, you know, organ preservation or not. I don't know if anyone has a different perspective. That's kind of a little bit our experience and our thoughts. I agree with both of you, Josh and Julio. There is a group in Australia that currently assessing treatment approach using CDNA, especially for patients that have clinical complete response. There are some limitations to the technology al bite. I'm not an expert, I think probably the least qualified person to talk about this topic, but from what I have read, if I remember correctly, a, not all patients so have detectable ctdna, ccf, DNA in blood at the baseline, similar to ca in. So I think this cell limitation we cannot use for all patients. B, what you're gonna do [00:56:00] if you have increase in cdd NA and then you conduct radiological analysis, so like CT scan, MRI, PET ct, you don't find anything, which is appears to be the case. From what I have read. And so detection is earlier compared to the development of macroscopic recurrence, either locally or distally. So what you gonna do with that? I think apart from the practical questions, there are some ethical questions. What do you say to the patient? Do you start chemotherapy even though early restaging using CT scan MRI or PET CT showed no signs of local distal recurrence? That's not a trivial question to answer. I think this needs lots of consideration, careful thinking, careful approach. I think it will be important like in colon cancer to maybe have a trial where upon increase or detect re detection of CDNA in patients with initial clinical complete response in suspicion of [00:57:00] regrowth, then you have randomization to either. Closer follow up or intervention. But the question is, what you gonna do? What are you gonna give chemotherapy, even though the patient will not have any, any metastasis or local recurrence, or you wait until this will be detected and then you give intervention because treatments completed, treatment is completed. And if patients have received TNT some of them cannot take any more systemic therapy, at least aggressively dose chemo. So I think there are loads of open questions, but it's certainly a very exciting scientific question. I completely agree. And let's just keep in mind we don't know the overall survival and we should wait for that. 'cause it could be that an MRD positive, CTD positive patient that we offer additional chemo to alters the biology. You might have taken some with resectable, oligometastatic disease and enhanced all the anti-death pathways of this cancer as you tried to injure it. And what you're left with is actually a more aggressive malignancy that is not surgically algo metastatic, but actually is [00:58:00] systemic disease that we can't resect. 'cause ultimately surgery is the cure of cancer, at least in colorectal cancer. So, I would say far too soon. The only other point I would add is the assay matters. There's tumor informed assays. You're looking for evidence of this actual tumor in the blood and there's the uninformed assays. I think we just kind of need to move beyond the uninformed assays. Those definitely are gonna give us, I think, the least information. I think this can be useful in the era of more aggressive therapeutic approaches for oligometastatic tumors. I think it's, it's a, it can potentially be a very valuable tool to recommend closer or more intensive follow up. So maybe every two months instead of every three months or every six months, with the aim of introducing early potentially curative treatment if the patient develops oligo recurrence or oligometastatic disease. But this is only one thought of mine. Sure. Well, these are, these are great thoughts and a [00:59:00] lot of exciting things as it relates to potential use for circulating tumor DNA. Also, a lot of exciting work in the biomarker space. You know, potentially using radios, AI-based approaches for sustained responders. Those that have a near complete response. We talked and touched a little bit about. Immunotherapy and maybe, you know, immunotherapy combined with chemo in addition to the sequence of potentially using short course versus long course. Some interesting studies that are yet to be published though, but were recently presented, were brought up. And so a lot of exciting studies as we think about what's the next frontier in total neoadjuvant therapy, in mismatch repair, proficient tumors, and how do we make these what is thought to be cold tumors hot? So we also touched a little bit about this idea of near complete response, and I think work from Oprah importantly showed that these patients can still avoid surgery because we know that about half of these patients can still preserve the organ and, and turn from a near complete response to a clinical complete [01:00:00] response given additional time. And so the trials that we've mentioned still have this opportunity for these patients with a near complete response to evolve to a complete response and safely enter the watch and wait. Pathway, and this will be validated in the ongoing trials that were, were recently mentioned. So a lot of important things that will still be validated and further studied as we move forward in the, in the modern era of PNT and locally advanced rectal cancer. This has been such an excellent discussion about multiple trials, multiple articles. I hope that our behind the Knife listeners take some time to absorb this information and also look up the articles and do some own reading. Main takeaways from today, we have learned that the German rectal cancer trial established preoperative chemo radiotherapy, followed by surgery as TME, as the standard of care, reducing local recurrence. But this left gaps in systemic disease control. This served as a building block for future seminal rectal cancer trials, which have changed the paradigm of treatment for patients with rectal cancer. [01:01:00] Second, many patients were unable to complete postoperative chemotherapy due to surgical morbidity or treatment delays, allowing micrometastatic disease to progress, which contributed to mortality. Total neoadjuvant therapy moves chemotherapy and radiation before surgery, ensuring patients receive full systemic treatment targeting micrometastases earlier, improving response rates, improved response rates led to exploration of organ preservation approaches, such as watch and wait. And patients are enthusiastic about this approach as it improves quality of life by deferral of surgery and avoidance of possible temporary or permanent stomas. Current studies are refining total neoadjuvant therapy regimens, such as short course versus long course induction versus consolidation, chemo triplet versus doublet chemotherapy regimens, exploring selective tion of treatment, organ preservation strategies, ctd NA based surveillance. [01:02:00] Integration of immunotherapy for more personalized treatment. Thank you to everyone. I really appreciate everyone taking the time to discuss with us today, the colorectal oncology surgery team. Looks forward to our next Behind The Knife Podcast, and thank you all for listening.