Clinical Challenges Management of mCRC ===

Welcome back to our Behind the Knife listeners. I'm welcoming back the colorectal oncology surgery team, including myself, Janet Alvarez, my colleagues, Winnie Zore, Phil Bauer, and Dr. J Joshua Smith. We have an esteemed panel of guests joining us today. First, we have Dr. Michael d Angelica. He is part of the Hepato Pancreatic O Biliary Surgery Service in Memorial Sloan Kettering Cancer Center. He is the Enit a helped chair in surgery, as well as the Vice Chair of education. We also have Dr. Kathy Ang. Who is part of Vanderbilt Ingram Cancer Center? She is the David H. Johnson Endowed Chair in Surgical and Medical Oncology, professor of Medicine of Hematology and Oncology, the VICC Associate Director for Strategic Relations and Research Partnerships, as well as the Executive Director of the Young Adult Cancers

Program. Lastly, we have Dr. Nina Sanford. She is part of the radiation oncology service at UT Southwestern Medical Center, the chief of gastrointestinal radiation oncology service, as well as an associate professor. Thank you so much for joining us today. Our topic of discussion is management of metastatic colorectal cancer. First, let me provide some context prior to our discussion. As we've mentioned in prior podcasts. Colorectal cancer is the third most common type of cancer diagnosed worldwide, and now the leading cause of death for patients under the age of 50. The American Cancer Society estimates about 158,000 new cases of colorectal cancer in this year. The incidences of early onset colorectal cancer has been increasing among younger adults, as we've also discussed on a prior podcast. Unfortunately, an estimated 20% of patients at presentation

will be diagnosed with metastatic colorectal cancer, the five year relative overall survival for patients with metastatic colorectal cancers, estimated to be 15 to 16% with most experiencing a survival of 24 to 36 months. The most frequent sites of metastases are the lymph nodes, liver, lung, and peritoneum. Currently up to a third of patients with metastatic colorectal cancer are limited to disease in the liver, which may be cured with systemic treatments and local regional SUR surgical removal of metastases. Now, first line treatment is determined by various factors including a patient's molecular profile, patient characteristics such as comorbidities, age, tumor burden. As well as me metastatic sites and their potential for resection. All right, thanks Janet. Uh, let's get to our clinical case. In the ed,

we meet a 60-year-old female. She's presenting with symptoms of constipation, abdominal pain, and bright red blood per rectum. She endorses unintentional weight loss. In the last year on colonoscopy, she was found to have a rectal mass, three to five centimeters from the anal verge. Consistent with invasive rectal adenocarcinoma on CT imaging, she is found to have lesions in the liver suspicious for metastatic foci. Dr. Ang, would you care to share your perspective on how systemic chemotherapy could be utilized for this patient? Definitely thank you for asking me. The error of chemotherapy really began with five FU followed by the addition of Irinotecan, which is a topoisomerase one inhibitor, and oxaliplatin, a third generation platinum agent, which is involved in DNA replication and transcription as part of the five F You base combined therapies, which are FOLFOX or Cape O, if you combine it with

capecitabine and fol fury. Whenever I see a patient with a primary tumor intact, like this patient as mentioned here, we need to confirm that there's no impending obstruction and we have clearance to proceed with systemic chemotherapy. So this is really where this is a multidisciplinary effort with our surgical colleagues and our radiation colleagues as well. We will then attempt to individualize care based upon the patient's performance status and evaluate other comorbidities. All patients, regardless of stage, are recommended to undergo testing for microsatellite instability, also known as MSI, high status, and for patients with metastatic disease. We also order next generation sequencing, also known as NGS, all of which will be discussed in the following section. For the majority of patients combined, chemotherapy is a standard of care. If a patient is believed to be healthy enough to tolerate. Treatment first line therapy consists of either Oxaliplatin based treatment, once again,

FOLFOX or CAP O, or irinotecan based treatment folfiri, or in a very healthy individual in which you want to reduce the tumor burden as much as possible. There is the consideration of FOLFOX Erie, which is Oxaliplatin, irinotecan, and five fq in one combination. Initiation of systemic chemotherapy is typically recommended before any consideration of surgical management of either the primary tumor or the liver lesions, especially if there is bi lobar liver metastasis. Now, regarding first-line chemotherapy, as mentioned earlier, we like to look at molecular subtypes, and a major advancement came with the addition of so-called targeted therapies. In this current age of precision medicine, the molecular profile, the patient's metastatic colorectal cancer tumor is important to determine their response and sequence of therapy to targeted agents. Patients benefit from their tumor tissue being tested for MMR or MSI status RAs. BRAF V

600 E mutation and HER two amplifications or mutations. It is important to note the molecular heterogeneity of this disease can influence a patient's response to targeted therapies. Despite having an actionable gene, alteration and survival may be impacted by the molecular subtype and predicts prognosis as well as therapies that may or may not be effective. An estimated 5% of patients have what's called MSI high or MR deficient, uh, tumor types and would be candidates for immune checkpoint inhibition with PD L one or PD one blockade with nivolumab and the CTLA four inhibitor ipilimumab or single agent pembrolizumab. Now, studies that have demonstrated this are from Keynote 1 77, which looked at pembrolizumab alone and then checkmate a HW, which looked at nivolumab and ipilimumab in combination versus chemotherapy, as well as versus nivolumab alone. And that was all in

favor of the doublet for those that patient population. Anti EGFR therapy or anti epidermal growth factor receptor monoclonal antibodies. Cetuximab and penit are also effective in patients specifically that are RAs wild type meaning kras, nras, and BRAF V 600 E wild type tumors. They're commonly combined with other chemotherapy regimens to optimize outcomes. And interestingly enough, tumor location is associated with response to EGFR inhibitors. With guidelines recommending their use in left-sided tumors. In summary, it is not recommended in patients with right-sided tumors or treatment naive tumors receive anti EGFR therapy as well as in the setting of having a RAs mutant tumor type. There's recent data that actually has demonstrated there's improved its survival, also in combination with folfox Erie and anti EGFR therapy. However, the PFS and the response rate

were very comparable between the two arms, so that literature is a bit more controversial and just recently came out in regards to the left-sided tumors benefiting from anti EGFR therapy that is based upon the phase three paradigm trial. Now there is some more really interesting new literature, which demonstrates that we know that RAs mutations occur in greater than 40% of metastatic colorectal cancer cases and are associated with a worse prognosis as mentioned and resistance to anti EGFR therapies. But there's been some new literature supporting the role of K-R-A-S-G 12 C inhibitors, such as raib and reib, and they've been tested as monotherapy and in combination and are currently approved in the refractory setting. There are ongoing trials that are looking at the combination. In combination with chemotherapy such as code break 3 0 1, which is soda raib in the frontline setting, and then crystal 10, which is looking at GRAS in the second line setting. Keeping in mind that K-R-A-S-G 12 C

mutation is very rare, it's only 2% of our patient population. And then one other thing I'd like to highlight. Obviously for those patients that have a RAs mutation, they aren't candidates for anti EGFR therapy. And if for patients that are MSI stable, they cannot receive immunotherapy. So in this case, we commonly provide anti-angiogenic agents, which are currently approved for, um, in combination with chemotherapy. And these agents bind to the vascular endothelial growth factor family or vegf. Family Bevacizumab, as many of you may know, it basically blocks anti-VEGF a and can be administered in combination with first line treatment and is often given in second line therapy as well, even after following progression of disease. It's really important to note that bevacizumab can lead to bleeding, arterial thrombosis, potential risk of bowel perforation, and delayed wound healing. So we like to discontinue it at least three to six weeks before a surgical procedure. And I think that's really important to just bring this up since Mike is also on this conversation and I, I'd

love to hear his thoughts about, you know, what his thoughts about duration of the chemotherapy should be and when does he like to hold the bevacizumab if, if it's been provided. Sure I can comment on that. If you're ever gonna proceed with liver surgery, in the context of systemic therapy, which is very, very common, that patients are on systemic therapy prior to considering liver surgery. For resectable metastasis, for bevacizumab, we like to hold it for about six weeks before surgery. That's two half lives. So in general, that will have minimal. Effect. And studies have shown that surgery is very safe if you're in, in that approximate window. In systemic chemotherapy, there's a wide variety of practices. Some people will wait over a month before stopping chemotherapy. We will wait two or three weeks sometimes, as long as there's no problems with neutropenia or other counts. Um, so I think at least. Two or three weeks off of chemotherapy. Some people prefer more. I think the more important thing is the duration of chemotherapy prior to surgery. If possible, the less is better in terms of

safety of liver surgery, if it's possible. Of course, sometimes you're trying to maximize response before considering liver surgery. Thanks so much. Excellent discussion. Let's bring it back to our case. So in our clinical case, further molecular testing does become available. We find out that our patient is KRAS wild type. A V 600 E mutated and HER two negative. Dr. Ang, which therapies would be available based on her molecular profile? Yeah, this is a great question and very timely because we have some new developments. B-R-A-F-V 600 E mutation, it's very specific to the V 600 E mutation. Historically, an MSI stable patient population confers a worse prognosis and often is less responsive to chemotherapy. It's about 9% of our patient population, and these patients commonly present their women with right-sided tumors and mucinous are poorly differentiated histologies. Um, they often frequently metastasized to the peritoneum and previously. Despite

the best therapy possible, including FOLFOX Erea, the median survival was only 12 to 14 months with systemic chemotherapy. But we now have some new data regarding combination of Cetuximab and Encorafenib, which is A BRA inhibitor, uh, specifically, once again the V 600 e, uh, tumor type, the original phase three B, uh, beacon trial randomized patients to who had had at least one prior regimen to Encorafenib Binimetinib, which was a MEK inhibitor. And Cetuximab, or Encorafenib plus Cetuximab, uh, versus a control group of systemic chemotherapy of either irinotecan and tux or folfiri. And what we found after prolonged follow-up is actually the doublet of Encorafenib and Cetuximab. Was superior in regards to the control arm, but also less toxic than the triplet arm, including Binimetinib, which had toxicities including diarrhea. So as a result, encorafenib and Cetuximab became approved in the refractory setting. But we've

had recent data from within the past year from a trial called Breakwater, which was specifically conducted. It was a phase three trial, specifically conducted in the BAF SCUs hundred E mutant tumor type treatment Naive. And patients were randomized to Folfox plus, encorafenib and Cetuximab, and there were three arms originally versus, um, chemotherapy or versus Encorafenib. Cetuximab alone. That arm eventually was discontinued. And what we learned is basically the median overall survival when you add Folfox to Encorafenib and Cetuximab. Has now improved to 30.3 months, which is a big breakthrough versus 12 to 14 months for standard chemotherapy. So in this case, this patient newly diagnosed, should receive FOLFOX plus Encorafenib, cet, cetuximab. And then actually just last week, the approval of. Fol Fury was just approved as well because they fulfilled the primary response rate of

64% versus standard treatment other molecular markers. HER two amplification is observed in two to 4% of all metastatic colorectal carcinoma. Patients, patients with treatment refractory disease have shown to benefit from HER two targeted therapy, which includes T Tutin and Trastuzumab, which was the original Mountaineer trial. And, and there's an ongoing Mountaineer three trial for newly diagnosed HER two amplified patients, and really wanna mention amplification is extremely important. Three plus by IHC, or two plus confirmed by fish. Let's say that our patient, unfortunately was treated locally, did not receive Cetuximab, but was treated with KPO and primary tumor and metastases don't seem to have responded very well. What additional options would be available to her in the second and even third line treatments? Sure. So in this patient with the B BRAF V 600 E mutant tumor type, we would then do the standard of care, which would be Encorafenib Cetuximab,

and that would be the standard of care in the second line setting. Now, if she was not, if she did not have the BRAF V 600 E mutation for second line therapy, as mentioned earlier, sometimes we continue on the treatment with anti-VEGF therapy. Once again, we have to evaluate the molecular profile, evaluate the tolerance of the treatment and the ECOG performance status of the patient. So in a non BRAF patient after progression of FOLFOX or folfiri, uh, patients with all RAs tumor types, so KRAS and RAs and BRAF wild type who have not received anti EGFR therapy before should receive. Combined treatment with irinotecan and anti EGFR therapy and then patients with K RRA s and nras meetin tumor types or have refractory disease following, uh, second line treatment. So in that case, bevacizumab once again is commonly continued into the second line therapy for patients that are having RAs muttin tumor type. Following second line therapy, three drugs are currently approved in the third line setting, which is Regorafenib, which is a multi targeted

TKI, tri Floridian and Traccel, or TAs 1 0 2 plus Bevacizumab is also approved in the third line setting. And for Quittin, which was an oral VEGF inhibitor, VEGF receptors one, two, and three is also currently approved in the United States for the refractory setting. So once again, these are kind of very different scenarios. So your braf, V 600, E and C. Seeking second line, you would do Encorafenib and Cetuximab. If you are a patient that had prior VEGF therapy, that's not BRAF F, you would continue on Bevacizumab into the second line setting. And then once again, if you're RAs wild type, you would receive anti EGFR therapy commonly in the third line setting if you've not received it in the first line setting. I know it's a little bit confusing, but there is a, a sequence to the therapy. Thank you so much, Dr. Eng, as you mentioned, yes, it's very in depth and very much going in the direction of personalized medicine when you incorporate the molecular targets for our patients. It's a very highly specialized field and I look forward to the

advancements in the near future. Now I wanted to go into the topic of incorporating surgical intervention, if at all possible for our patients. So, Dr. Smith, would you be able to comment on how we would incorporate surgery? Sure. Thanks Janet and thanks, uh, Dr. D Angelica and Drang, and look, looking forward to hearing from Dr. Sanford as well, uh, here shortly. But, you know, in the first line, we typically think of a surgery first approach. Very rarely, uh, especially when the primary tumor is either a rectal tumor like it is in this case. Or the colon primary is otherwise asymptomatic. And we think of metastatic colorectal cancer as resectable when the primary tumor and then all metastatic lesions are amenable to safe removal. But we must keep in mind the technical aspect of achieving an R zero resection and the patient's ability to undergo surgery, their performance status, and then of course the extent of disease, and then careful consideration of the molecular

profile tumor biology. And then as Dr. Yang mentioned early on, it's really critical to have a multidisciplinary discussion about these patients so that we are selecting the optimal treatment approach and also the sequence of therapies. As you can tell, it's, it's critical and really need all the experts in the room to decide what's the the next best step. Now in those cases of unresectable metastatic colorectal cancer, systemic chemotherapy is the preferred first line. As has just been very nicely discussed, and current data does not support resection of the primary tumor. To further emphasize this, a surgery first approach in these cases can be pursued, but this is typically in patients with either obstruction, significant bleeding from the tumor, or impending perforation. All of these. Are scenarios which would prevent, uh, an opportunity for the patient to safely undergo, uh, sustained systemic chemotherapy. So this brings me to Dr. D Angelica. Can you give us

some of your historical perspective for the management of colorectal liver metastasis, where we started and where we are, and then your views on workup management, resectability, and even thoughts on sequencing of treatment. Yeah, absolutely. Thanks Josh. It, it is fascinating to hear that. Beautiful discussion of all the systemic options that are available that Dr. Ang just went through, uh, so comprehensively and really beautifully. But it's very interesting when patients have limited liver metastases that, let's just say two or three lesions that are technically resectable. The potentially curative treatment is surgery to remove them. There are some recent data that if they're small and in the proper location and in a well-selected patient, percutaneous ablation can be used. But the historical data shows that resection of liver metastases when they're limited, and this is a small subset of patients, is potentially curative somewhere on the range of 20 to 33% depending on how you

select your patients. So surgery is really. Something to discuss. The workup has to be detailed. I, I think it's really important that we just don't say, get a standard CAT scan. If we think there's limited and resectable liver metastases. A standard CAT scan's probably not adequate. We need liver directed imaging, which. Includes high quality liver specific CAT scans, and nowadays we use a lot of EO VST enhanced MRI, which can find very small lesions that are often not seen on CAT scan, and that really helps to sort of work up the patient, get a sense of whether they have extra pad disease because the resection becomes less relevant when there's extra hepatic metastatic disease. And also helps us assess the extent, the extent of the tumor burden in the liver and whether surgery's even feasible. Or something to be considered. And so, you know, the imaging's very, very important. The, the imaging should include a complete assessment of the primary tumor as well as Dr. Smith was talking about. Rectal

cancer becomes very different from colon cancer. I think. You know, we were saying that systemic chemotherapy is the backbone of the treatment, which it is for the great majority of patients with metastatic colon cancer. However, when there's limited liver metastases and it's a colon cancer primary tumor, and shrinking the tumors is not really necessary. Surgery should be discussed and even considered upfront. The the, the difficult thing, and I'd love to hear Dr. NG's thoughts on this, is that in that situation with colon cancer and limited liver metastases that are resectable. Systemic chemotherapy in multiple randomized trials has not been cha found to change overall survival in any meaningful way. It may delay recurrence-free survival or improve it slightly, but the overall survival is the same. So surgery is a really big part of the discussion for limited. Colorectal metastases. And again, I wanna stress that this is a relatively small subgroup of the overall situation. You know, Dr. Ang was discussing systemic therapies, which applies to the great majority of patients. And even though a lot of the recurrence

patterns or the metastasis patterns are in the liver, really the majority of those patients, or at least the significant proportion of 'em, have extra hepatic metastatic disease or unresectable disease. And when, you know, the discussion I'm having about surgery is not relevant to them. In terms of sequencing, if you're gonna give chemotherapy, it should be short for colon cancer and then go to surgery. The longer the systemic chemotherapy is given, the higher the risk of complications for liver surgery. 'cause the systemic therapies, at least the cytotoxic chemotherapy can be toxic to the liver. Can cause fatty liver. It can cause sinusoidal obstruction syndrome, which can cause a relative portal hypertension. And in randomized trials, preoperative chemotherapy was associated with a slightly higher risk of postoperative morbidity for liver surgery. Rectal cancer, as others can talk about in more detail, is a very different situation because. As we all know, we don't always have to operate on the rectal tumor if they have a great response to systemic therapy. So a lot of the initial upfront treatment when there's a rectal primary in place

has to do with, uh, the optimal treatment for the rectal tumor. So my first question is often to the colorectal surgeon and the medical oncologist, before I consider surgery on the liver, what do you need to do to optimize management of the primary tumor? Now for unresectable liver metastases, there are a few other very important considerations. In addition to all the systemic options that Dr. Ang just went through, one would be trans arterial radio embolization. However, in most cases that is not been shown to improve overall survival, although it can help control liver disease in certain refractory situations. The other thing that we do a lot of is hepatic artery infusional chemotherapy. The drug we use is fluorine. Which is infused through a surgically implanted pump into a branch of the hepatic artery and gives basically very high dose chemotherapy that's completely extracted by the liver, so you can give high dose chemotherapy. In the first line setting, this is associated with response rate as high as 90%. In the second line setting,

somewhere between 50 to 75%, and even in the refractory setting, probably response rates in the order of 30%. Patients can live a very long time, although I should stress that the majority of the data that that comes from is from a single institution. My own in New York City, Memorial Sloan Kettering. And in highly selected patients. So whether that will be expanded to the rest of the population is really to be determined and the those hepatic artery pump chemotherapy programs are expanding across the country and internationally. Pump chemotherapy can also downstage patients such that they can become resectable with curative intent, which is a very important outcome, I believe. However, pump chemotherapy should be. Manage in the context of the known toxicity of biliary sclerosis, which happens in approximately 5% of patients. It can be a very significant complication. So I think hepatic artery chemotherapy is something very much to be considered in these patients in the context of multidisciplinary care with a medical oncologist and colorectal surgeon. Thank you for that. And then Dr. D Angelica, how do

you best determine resectability for colorectal liver metastases? Yeah, a very important question, but a somewhat loaded question. I think most of us in the, in this field kind of think of it two ways. There's technical resectability and sort of biologic resectability. Technical resectability is based really on the technical aspects of liver surgery, and that really is based less on what you remove, but what you leave behind. So as long as you can remove all the tumors and leave a sufficient liver remnant. That can regenerate safely, then you're technically resectable. However, there are certain situations where you are technically resectable, but your response, your recurrence rates are so high that someone might consider them biologically unresectable. If there's, you know, when you start getting to the number of tumors where there's 7, 8, 9, or 10 tumors, surgery can be a helpful treatment. However, the recurrence rates are very, very high. So resectability starts to come into question as the number of tumors goes up to very high numbers.

Even simple things like your CE, A level, very high, CE, a levels are associated with very high recurrence rates, and some may consider those biologically unresectable. Um, you can use things like the clinical risk score and various scoring systems that combine, uh, different biologic criteria. And so we really kind of stratify them into potentially curative and non potentially curative in the patients with, say, less than four metastases, no extra hepatic disease, low CEA levels, and a resectable primary tumor. That's a potentially curative operation and completely indicated, but as you get to the very high risk patients, it's used selectively with different objectives for management of their disease in the long term. There is a trial looking at, uh, liver directed therapy. Is that correct? And then my second thought, Mike, is can you just give us an update on where you think you, we are with, um, use of transplant in patients who may have by low bar and innumerable lesions. Any thoughts on how those patients should best be approach. Sure. I'm

happy to talk about that. It's very interesting, a after, you know, the use of hepatic artery, infusional chemotherapy at really one institution for many years, there is now a really growing interest in this across the country and across the world. And we've now developed an hepatic artery infusion consortium. Uh, there's probably over a hundred centers now doing it. And one of the most important things that consortium has done is to develop cooperative group multi-institutional trials, and one of them is EA 2222. Looking at persistently unresectable disease, uh, after receiving first-line chemotherapy for three to six months and being randomized to pump chemotherapy versus standard of care, systemic chemotherapy, we're currently accruing to that trial and we're currently developing other trials in the adjuvant setting, which we haven't discussed very much, or even novel indications. So I think there are ongoing trials, which is very exciting 'cause all the previous trials were really done at Memorial Sloan Kettering, and it's very important that these trials get done. In the context of multi-institutional real world

treatment paradigms. Transplant is actually a very interesting topic on this. The, the story is somewhat long, but I'll try to summarize it quickly. Transplant for this disease was tried many years ago, probably in the 1980s and nineties, and did really terribly probably due to poor imaging and poor selection and in, in an interesting turn of events over the course of the last 20 years in Norway, a number of single arm trials were done in highly selected patients with. Very prolonged stab stability of disease with liver only metastases and showed feasibility and really promising long-term outcomes. When that data was presented and published extensively, a lot of us felt that a lot of the outcomes might have been all based on selection. However, a recent trial from Europe based mostly out of France called the Trans Met Trial, compare transplant to systemic therapies. Uh, in the context of stable disease, most patients had stable disease for at least a year,

and liver only metastasis showed a very significant survival benefit to transplant. Now obviously transplant is a huge issue with multiple issues that come along with it. Like, can you get a, uh, a liver for your patient? Does it have to be a living donor? It obviously has to be a very young and healthy patient who is stable on chemotherapy for a long period of time. They often require that the primary tumor has been removed, and there are other selection criteria as well, but in highly selected patients, liver transplant is probably going to play a role in the management of liver confined unresectable metastases. It is interesting that while these patients live longer, the great majority of them will recur after transplantation. However, the majority of them are small numbers of metastases in the lung, which can often be managed. With ablation or surgery, and these patients can live many, many years. So it's a fascinating turn of events and a real, and and a testament to a really bold trial done in Europe that showed US survival benefit to transplant. And we do

refer patients for this when they're, when they fit the right criteria, which is a small group of patients, but when you see them, you should really consider. Yeah, that's super helpful. Thanks so much. Just one quick, I guess, tangential point to what Dr. D Angelica was saying is typically if somebody is going for transplant, we, we would resect the primary tumor, uh, prior to, uh, transplantation. Thank you so much for that interesting discussion. Dr. Smith, what factors play a role in determining the resectability for the primary tumor? Sure, I'm happy to get into that. So, resectability for tumors in the colon is rarely an issue. You know, typically a, you know, SQL tumor or a, a sigmoid or a left-sided tumor. But we do manage some patients with. Clinical T four tumors, those invading or encroaching on other organs like the bladder, stomach, or pancreas carefully. And these require a very, uh, multidisciplinary approach with surgical planning and then potentially achieving downsizing and appropriate

tumor response so that we can ensure a margin negative resection. And we very often. Coordinate for a staged approach or a sync, a synchronous approach with our HPB colleagues, and that's assuming there are other potential options for the, the liver or the lung. Um, should there be disease outside of the liver, for example? Now, rectal cancer, for example, in this case is a completely different scenario and features such as lateral, pelvic sidewall. Distal tumors also T four Disease involving other organs or EMVI and a high degree of nodal burden factor into the selection of how we best gain local control. And we want to optimize, uh, the management of the disease sites as it relates to the metastatic disease. This is really critical for any chance. To achieve a potential cure where, and we certainly work closely in a multidisciplinary fashion with our radiation oncology colleagues, medical oncology colleagues, and HPB and even thoracic colleagues to select the modality that gives us the best chance

for local control of the primary tumor and then address the metastatic disease. And certainly we're careful to introduce local control options at the appropriate time. And this is a good segue for, for Dr. Sanford to tell us where we think that either a short course radiation approach or a long course chemoradiation approach is, uh, appropriate to obtain optimal response to the primary tumor. As you said, uh, Dr. Smith we're lucky to have an expert in radiation oncology like Dr. Sanford here. So you know, in this case of a low rectal tumor with metastatic disease. What are your thoughts on the use of short course versus long course radiotherapy and how that fits in sequencing wise with systemic chemo in this patient with metastatic disease in the liver? Yeah. So, uh, first of all, thank you so much for including me in the discussion. I've already learned so much from the other speakers here. Yeah, so just to give some background, I think the listeners are aware, but short courses, five grade times, five fractions daily, so that's done in a week. Um, long course is 1.8 to two gray, or five to six

weeks to about 50 to 54 grade total. And for me, I think the decision between the two in the. Static setting, um, really depends on three things. The first is the burden of disease elsewhere outside of the pelvis. Obviously, we, you know, we would assume that the patient is, uh, responding that their, their disease is not progressing for considering consolidative local therapy. But the exact burden or extent might, will probably influence how comfortable you are giving them a break off of multi-agent systemic therapy and how long you want. To take for radiation. The second would be the extent of residual disease in the primary tumor of really how well it's responded to stomach therapy and all those risk factors that Dr. Smith talked about. And that would predispose a patient to have a positive margin if those are still present after chemotherapy. And then the third, um, that has become increasingly important, I think in 2026, is whether or not the intent of the radiation is pre-op or definitive intent. So generally, for pre-op radiation, if there are no high risk. Features for local recurrence

and we generally preferred short course radiation, um, to get it done quickly, maximize time off of chemotherapy, um, especially if there are untreated sites still present. However, if there are those risk factors for positive margin T four and contacting nasal rectal fascia, ator nodes, et cetera, then we may need a longer. Course of treatment, and in these situations we try to address the rectum last. Now the final thing I'll talk about is that there, as I'm sure everyone's aware, there's been growing interest in organ preservation for all stages of rectal cancer. But you know, perhaps especially for stage four, especially in this, like in these cases, a distal tumor, it makes sense because since these patients unfortunately, have a higher risk of distant recurrence, even if we've addressed all sites. The idea of having a permanent colostomy only to potentially later develop metastatic lesions elsewhere is understandably less appealing. So, you know, the data are not as established as in locally advanced rectal cancers like the Oprah trial and whatnot. But I think, you know, a lot of us are comfortable

extrapolating from some of those studies. And if that being said, if the treatment intent is definitive chemoradiation for stage four tumors, then we would recommend long course of radio sensis and chemotherapy to get to a higher total dose. Well, let's make it even more difficult. Let's say in addition to her liver lesions, she's also found to have lung lesions consistent with metastasis. What would be the role of radiation therapy in this scenario, and would you consider using SBRT? Yes, I would. So yeah, we start with systemic therapy to understand the biology disease, see how it responds if they have good response, or at least stable disease and nothing new. Start thinking about these local treatments. I think with respect to La Med specifically, we do often recommend consolidated SVRT. You know, I like how Dr. D Angelica framed the decision with regards to the liver. Kind of dividing into biology versus technical feasibility. And it's really the same for me for SBRT. You know, with that I generally, you know, don't treat maybe more than five lung mets. If, you know,

patients really have more than, it probably reflects more disseminated disease. Even if a cult and, you know, other markers like which previously mentioned would be a high ca. But for us, also a practical issue because if you are treating several tumors kind of scattered throughout the lung, um, then you are exposing more normal lung to irradiation. Of course, depending on where they're located, how spread out they are, the size of them. So I kind of look at the big picture with regards to disease trajectory and the location of the tumors. How many, it's really not a card cutoff, but kind of go on a case by case basis. But presuming that we do offer radiation has delivered in, um, anywhere between one to five fractions. I try to do more and more single fraction when able, and it's generally really low toxicity, so we often are able to flip it in sort of between systemic cycles or other treatments, you know, wherever the patient has a gap. You know, maybe at this point I'll just sort of segue sort of back up a step and sort of generally talk about the role

of SBRT in, uh, metastatic or oligometastatic colorectal cancer. Obviously this is a big topic, but I think I just wanted to emphasize a few points. The first is sort of defining what oligometastatic is. And I think has already been alluded here. It's really more a concept than a formal binary definition. And the idea is really to identify patients with metastatic disease burden who are less likely to harbor disseminate occult tumor burden. So-called like what we see on the scans is the tip of the iceberg because we think that in these patients aggressive local therapy might have the potential to alter disease trajectory, provide long-term tumor control, and even cure in some. In 2026, I don't think we are perfectly able to identify who this patient population is, but some surrogates. You know, we talked about number of tumors, number of organs, and which like, you know, if we, a patient has disease in the peritoneum, we think of that as more disseminated, you know, when the metastatic tumors appeared at diagnosis or after a long interval stability, sort of the overall disease trajectory.

So it's really a number of factors that we. Try to take into account to say if this patient is oligometastatic or not. The second point I, uh, also alluded to to above is that SBRT is generally convenient and low toxicity, and really the majority of patients doesn't mean the risk is zero, but most patients report really. You know, few side effects I would say, especially the lung tends to be very well tolerated and very low side effects. So when we think about sequencing, I think two things come to mind. The first is that we can try to slip it in between other treatments, and then two, you know, I think when we think about integrating. With potentially more invasive local therapies such as surgery to the primary. We might do radiation first 'cause it's, you know, potentially less toxic to give sort of more a test of time before committing to a surgical procedure. And then the last point, which we'll segue into our next discussion is, you know, we wanna know what is the data for SVRT in oligometastatic colorectal cancer. And I think we are getting there. I'll

admit that most. Of what we have right now is sort of like these single arm studies that are very promising, but I know you know, we all know that the major limitation here is selection bias. There was a phase two randomized trial, the SRE Comet study showing better overall survival in metastatic cancer with the addition of CRT, but this was across several disease sites and I think there were about 18 to 20 colorectal cancer patients. So the subset is quite small. There are a lot of challenges to accruing to these studies, which I won't get into, but as will now be described, we do have an ongoing phase three, a randomized trial, which we're all really excited about. Comprehensive local radiotherapy is being prospectively evaluated in the evaluating radiation ablation and surgery. The ERASER trial at Ohio State led by Dr. Eric Miller. This ongoing phase three study examines whether the addition of total ablative therapy or TAT defined as the eradication of all metastatic sites through a combination of stereotactic

of ablative body radiotherapy. Surgical resection or thermal ablation in conjunction with standard systemic therapy, improve survival in patients with limited metastatic colorectal cancer. Eligible patients with up to four sites of metastatic disease are randomized to receive systemic therapy alone, or systemic therapy plus TAT with overall survival as the primary endpoint. The trial reflects a growing paradigm in which aggressive local therapy is applied to all sites of metastatic disease. In an effort to delay progression, prolonged survival, and potentially achieve long-term disease control in selected patients with oligometastatic colorectal cancer. Finally, I think it's important to note that palliative interventions remain a critical component of care for patients with metastatic colorectal cancer, particularly for those that have a, have highly symptomatic disease and metastasis, not amenable to curative intent therapy. Systemic chemotherapy remains the cornerstone treatment in this setting and is

typically administered with palliative intent to prolong survival, control, tumor burden, and alleviate symptoms. In addition, regional radiation therapy can provide effective palliation of pelvic pain, bleeding, or mass effect from locally advanced rectal tumors can also control symptomatic lesions such as painful bone metastases or spinal cord compression. Endoscopic approaches are also intriguing, including those such as self-expanding metal stent placement that may relieve malignant and large bowel obstructions and help to avoid emergent surgery in selected patients. While diverting, ostomy or limited surgical procedures may be required for refractory obstruction, perforation, or fistula image guided interventions such as percutaneous ablation and embolization have also begun to play a role in cases of bulky symptomatic disease. Together these strategies underscore the importance of multidisciplinary palliative management focused on symptom relief and maintenance of quality of life, while systemic therapy addresses overall disease burden.

Thanks, Phil. This has been a really excellent in-depth discussion of the multidisciplinary approach to metastatic colorectal cancer. In summary, our main takeaways from today's conversation, metastatic colorectal cancer has a poor prognosis. However, a select group of patients can achieve cure with a combination of systemic therapy and surgical resection. Modern day treatment is driven by precision medicine as Dr. Ang. So kindly went into a very detailed discussion about first line, as well as second and third line treatment. This is based on molecular profile and does predict a patient's prognosis as well as treatment response. Surgery and liver directed therapies can significantly approve outcomes, and there is an expanding role for radiation as Dr. D Angelica and Dr. Sanford also described. For us. Overall, the management of metastatic colorectal cancer requires a multidisciplinary approach

integrating systemic therapy, surgery, radiation therapy, and consideration of palliative care to optimize survival and quality of life. Thank you so much everyone for joining us today. I hope that you have learned the overall management of metastatic colorectal cancer and we appreciate you tuning in. Thank you.