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Benjamin L. Schlechter, MD: Hello. I'm Dr Benjamin Schlechter, and welcome to Medscape's InDiscussion series on colorectal cancer. Today we're discussing systemic therapy for advanced colorectal cancer with Dr Diane Savarese. Dr Savarese is a recognized expert in gastrointestinal (GI) oncology and has recently retired from a long career in which she served as the GI oncology editor at UpToDate.
She was a senior member of the Division of Hematology and Oncology at Beth Israel Deaconess Medical Center and helped lead the oncology program there. And she was also a member of the Faculty of Medicine at Harvard Medical School. She's well known for her encyclopedic knowledge of GI oncology in general and colorectal cancer in particular.
Before we go to our discussion, Dr Savarese, I'd love to hear a bit more about your path to becoming a GI oncologist.
Diane Savarese, MD: It was actually quite circuitous. My undergraduate degree is in pharmacy. When I finished my 5 years of pharmacy school, I took a part-time job as a cancer researcher at Roger Williams Hospital in Providence, Rhode Island, where I worked with Ellen Spremulli and Dan Dexter, who were very instrumental in the very beginnings of tumor biology.
Subsequently, I applied to medical school. During my residency at Johns Hopkins, I was involved in the care of a lot of cancer patients and met wonderful people like Ross Donehower, who really stimulated my interest. I joined the fellowship program at the National Cancer Institute (NCI); that was during the Charles (Snuffy) Myers and Bruce Chabner years. At that time, AIDS and AIDS-related cancers were very prominent. It's because of that, that I didn't become an infectious disease doctor. That really was my initial love.
I took a job at UMass after that, in 1989-1990. I focused mainly on prostate and GI cancers because that was the niche that needed to be filled there. After 10 years there, I was lured away to UpToDate by Bud Rose, who is the founder of UpToDate, and he was a nephrologist at UMass. I was the inaugural editor for oncology. It's hard to believe, but I actually did all of solid tumor oncology and Hodgkin disease for about 10 years. I subsequently took a faculty position at Harvard and a part-time clinical position at Beth Israel, again, focusing mainly on sarcomas and GI cancers.
Schlechter: I have to say as a former fellow of yours and as someone who still calls you for advice, I think you are really one of the most valuable voices in this community.
Let's talk about colon cancer here. When we think about advanced colorectal cancer, there's a lot of categories that we can talk about. There are ways to divide out this disease. We've addressed important but less common subtypes, like HER2-amplified disease and the role of immunotherapy. Those are valuable and important discussions, but they really dig down on a few percent here or there. When you're seeing an average patient with colorectal cancer, how do you break down this patient population? How do you think about these individuals?
Savarese: I think the most important broad concept is that there is no such thing as a one-size-fits-all approach to advanced colorectal cancer in the initial therapy. The way I break down patients in treatment decisions is in three ways.
I look at the molecular characteristics of the tumor, and the most important of those in the front line are RAS and RAF mutations and deficiency in mismatch repair (MMR), which of course indicates the likelihood that the tumor will respond to checkpoint inhibitor immunotherapy.
There are a couple of other broad categories that I consider. One of them is the burden and location of disease, as well as patient factors. The most important patient factors are fitness level, which depends on comorbidity and performance status, and the patient's values and preferences have got to be considered tantamount in all of this, especially when it comes to counterbalancing the toxicities and survival benefits of these treatments.
One of the more important things is the status of the patient's tumor in regard to potential resectability. I'll give an example of how that works. If you have a patient who has a potentially resectable tumor, but initially unresectable disease, you want to choose a regimen that has the highest response rate you can get, because that's the way you're going to get that patient to a resectable state and potentially giving them the possibility for long-term survival.
In contrast, if you have a patient who doesn't have a hope of having resectable disease, the most important endpoint to focus on is progression-free survival because you want to achieve as long a period of disease control as is possible so that you can maximize the number of treatment regimens that you're able to offer to that patient.
Schlechter: Excellent. How do you think about your initial decisions: for example, doublets vs triplets, right sided vs left sided? When do you choose FOLFOX or FOLFIRI and FOLFOXIRI? Let's start with the chemo backbones before we talk about some of the monoclonals.
Savarese: The chemo backbone nowadays entails a description of triplet therapy, which includes oxaliplatin irinotecan in conjunction with bevacizumab or an anti–epidermal growth factor receptor (EGFR) agent. Those are the two classes of biologics. The issues that come into play are dependent on the robustness of the patient population because FOLFOXIRI, the triplet combination, is a pretty tough regimen, especially when it's combined with bevacizumab.
We want to make sure that we're not going to trash the patient in trying to trash the tumor, because there we've not made any inroads at all. The first decision-making point is, can this patient tolerate the heft of triplet therapy? And then the second factor is where the clinical situation is. In my eyes, that is based on the resectability of the primary tumor.
Triplet therapy, especially combined with a biologic agent, has among the highest response rates that we see with systemic chemotherapy in metastatic colorectal cancer. But you have to be careful about what you choose. I'll give you an example of that. There's some data for patients who have potentially resectable liver metastases showing that if you combine a regimen that includes oxaliplatin, and that includes both the triplet regimens and the doublet, with an anti-EGFR agent, the overall progression-free survival may actually be worse than if you use a different type of combination therapy.
So we have to be careful about which agents we combine. Here is a good illustration of the conundrum that we as oncologists face. Back in the 1980s and 1990s when I first started my practice, we only had 5-fluorouracil (5-FU) and the average survival there was roughly 6 months. Starting in 2000, when irinotecan was approved, oxaliplatin followed in 2002, we now have a tremendous number of active drugs in metastatic colorectal cancer. But it has led to significant challenges, the "riches" that we now have. One of the biggest challenges is that we're not really sure how to optimally sequence and combine all of these agents together.
Another is that sometimes when you combine all of the agents together, you end up with high response rates, but a very modest impact on survival and a lot more toxicity.
The third thing is the toxicity level. Many patients look at that and according to their values and preferences, it's not a situation that they really would like to be — having more toxicity and impaired quality of life and only getting a little bit of benefit.
The one situation where I think it's clear that the triplet therapy is a benefit, especially in combination with bevacizumab, is in people who have BRAF-mutated tumors. That's where there are data suggesting that FOLFOXIRI plus bevacizumab overperforms doublet therapy plus bevacizumab in terms of objective response rate, overall survival, and progression-free survival. And even though it has a higher side-effect profile, those three outcomes are important for that category of disease, which has a very poor prognosis.
In the setting of potentially resectable or borderline resectable metastatic disease, I would always choose the triplet regimen with a biologic agent.
Schlechter: That gets us to some of these trials that we learn about as fellows and that we see in practice. We see summarized in your section in UpToDate, where we have the STEAM trial by Hurwitz and colleagues published in The Oncologist in 2019, and TRIBE, which was by Cremolini and colleagues and published in The Lancet Oncology, that STEAM was FOLFOXIRI vs sequential FOLFOX and FOLFIRI, which I thought was an interesting design.
And the benefit was moderate, but there was something there, especially as you pointed out in the mutated cancers and the same thing in TRIBE, which was against FOLFIRI. There was a benefit, but it was hardly as impressive as I would hope. For that much extra bang, you don't get a lot of bucks.
Savarese: That absolutely correct. One of the areas that is especially unclear, even today, is what exactly bevacizumab contributes to that triplet regimen of FOLFOXIRI, because there's never been a trial that directly compared FOLFOXIRI with or without bevacizumab. As you know, there are significant toxicities when you add bevacizumab, especially in people who are over the age of 65.
The only data we have come from a pooled analysis of seven trials assessing the benefit of bevacizumab in conjunction with chemotherapy. The median overall survival was just 2 months greater with the addition of bevacizumab to a variety of oxaliplatin- or irinotecan-based regimens. The benefits of all of these biologic agents have shrunk over time, whereas our understanding of their toxicities has expanded over time.
That complicates the choice of therapy.
Schlechter: When you're facing a patient with advanced disease — multifocal disease, for example — and they've had prior adjuvant oxaliplatin. Does that inform your decision for a triplet regimen vs a doublet regimen?
Savarese: I think the choice in somebody who's had prior adjuvant therapy boils down to, are you going to give them FOLFOXIRI or FOLFIRI? And the problem with giving FOLFOXIRI is that we're assuming that because of the prior adjuvant FOLFOX, what has grown out in the recurrent disease is a population of predominantly oxaliplatin-refractory colorectal cancer cells. In my view, giving both irinotecan and oxaliplatin is not necessarily going to mitigate that. I think in that situation, I would probably stick with just FOLFIRI, and consider adding an anti-EGFR agent if you have a wild-type tumor and your tumor is not on the right-hand side or adding an anti-angiogenic agent at that point.
Schlechter: Speaking of the anti-angiogenic agents vs the EGFR inhibitors. I always struggle with the idea that the thing you give first is thing you give longest. We have three prospective randomized trials supporting the use of EGFR inhibitors in the first-line setting.
Actually, we have more than three. We have, the CRYSTAL study from Van Cutsem and colleagues published in The New England Journal of Medicine in 2009. We have the MRC COIN trial published in The Lancet Oncology paper in 2011. That was FOLFIRI with cetuximab and then FOLFOX with cetuximab. And then, of course, we have the PRIME study looking at FOLFOX and panitumumab.
These are highly active drugs, but they add a lot of toxicity in the first line. That's the thing the patient's going to be on longest. It's also very apparent toxicity. In the breast cancer world, alopecia is the way you see the side effect of therapy. In the colon cancer world, for EGFR inhibitors, we see the EGFR rash right on the face.
How do you think about when to incorporate those agents, which are both effective and toxic, in the first line vs the second line?
Savarese: I think the whole concept of whether or not every patient should get a biologic agent for frontline therapy is an extremely controversial area. As you point out, there's a lot of toxicity involved. Initially, when all these biologic agents came into our level of clinical trials, the trial suggested a lot more benefit from the addition of a biologic agent — either an anti-EGFR agent or an anti-angiogenic agent — than we're currently seeing. Part of the problem is that the initial approval of bevacizumab was in conjunction with IFL, which is a bolus irinotecan-containing regimen that is probably less effective than one of the short-term infusional FU regimens that we use now, such as FOLFIRI and FOLFOX.
As time has gone on, and bevacizumab has been combined with more and more active chemotherapy backbones, the benefits of those drugs have really declined and the toxicity profile has increased. The same exact thing has happened with EGFR inhibitors. I personally use patient values and preferences to decide on whether to add a biologic in the first-line treatment. One of the important concepts of treating metastatic colorectal cancer is that the best survivals are seen in patients who are exposed systematically to all effective agents. Remember, I said back when I first started, median survivals of metastatic colorectal cancer were 6 months. Well, now in the most recent report of the FIRE-3 trial, in KRAS wild-type tumors receiving combination of a doublet plus an EGFR agent, the median survivals are approaching 29 months. That's a pretty impressive difference over a 30-year period of time. Those survivals are achieved in patients who are systematically exposed to all active agents.
One of the problems with giving these agents up front is that patients tend to be less likely to receive more chemotherapy afterward because they're tough on people. I prefer sometimes to start with a cytotoxic chemotherapy backbone and then add a biologic agent for second-line therapy, depending on what was given firsthand, whether or not the RAS/RAF mutation status is known, and considering wild-type vs mutated and also the sidedness of the tumor.
Schlechter: We have several studies: CRYSTAL, FIRE-3 and PRIME. All have shown this interesting finding that the biologic predictive marker of RAS/RAF wild-type cancers doesn't follow through on right-sided cancers. Right-sided cancers can resist EGFR inhibitors in interesting and unexpected ways.
How do you think about that? Do you just try it because you can, or do you really think we should avoid these agents on right-sided cancers?
Savarese: The tumor-sidedness issue is something that's been percolating for a very long time, and initially the data came from subgroup analyses of clinical trials that were not looking at tumor sidedness as an endpoint. A preponderance of evidence now supports the view that if you have a right-sided tumor and the definition of a right-sided tumor is one that is proximal to the splenic flexure, these tumors are relatively refractory to first-line therapy with an anti-EGFR agent.
We're only talking about first-line therapy here. There are very few data at all on the effectiveness of EGFR agents for right-sided tumors in later lines of setting. The best data we have now come from a very well-done pooled analysis that was published in JNCI back in 2021, in patients with previously untreated metastatic colorectal cancer.
Among the 500 patients who had RAS wild-type tumors compared with combinations of cetuximab plus chemotherapy, the use of bevacizumab plus chemotherapy led to a more than doubling of the median overall survival: 26 months vs 12.5 months. That's an astonishing difference. In contrast, if you looked at left-sided tumors, there was absolutely no difference between cetuximab plus chemotherapy or bevacizumab plus chemotherapy.
The bottom line is, if you are going to use a biologic agent as part of your first-line regimen, if a patient has BRAF, RAS, wild-type tumor, and a right-sided primary tumor, I would choose bevacizumab, whereas if they have a left-sided primary tumor, you can either choose bevacizumab or an anti-EGFR agent — again, depending on the patient's values and preferences.
Schlechter: We live in an era where we're trying to refine toxicity and refine benefit. It seems clear that escalation of therapy in the first line is not for everyone, and we've seen this in a number of ways culturally in colon cancer — even going back to early-stage disease, where we have the IDEA Collaborative looking at de-escalation of 6 months vs 3 months of adjuvant therapy. We have PROSPECT in rectal cancer. We're trying to avoid the toxicity of radiation in a subset of selected individuals. In the advanced disease setting, we also face the conundrum of when to stop, how much chemo is enough, the role of maintenance therapy, and the role of observation off of therapy. How do you palliatively de-escalate in the advanced disease setting? How do you do that?
Savarese: I think of this as a question of intermittent vs continuous therapy. Up until a few years ago, we basically treated people with the first-line regimen until they developed progressive disease. And in some cases, they were on chemotherapy for years, because if they had particularly indolent disease or a low amount of tumor burden, they could be on therapy for quite a long period of time and it was unclear when the stopping rule was.
But largely as a result of efforts to diminish the toxicity of therapy, folks have been looking at different ways of mitigating it — especially oxaliplatin neuropathy, which is the cumulative and often dose-limiting effect of oxaliplatin. All of the trials looking at intermittent therapy initially focused on oxaliplatin, and they followed two paths.
They followed the path of maintenance strategies, which is giving an oxaliplatin regimen for a period of time and then taking the oxaliplatin away and leaving the patient either on 5-FU/leucovorin modulated alone with or without bevacizumab, or 5-FU/leucovorin with bevacizumab.
There's also some data on when EGFR inhibitors were part of the initial treatment. Taken together, all these studies support the view that survival is not adversely affected by using periods of maintenance chemotherapy without oxaliplatin, and the toxicity is clearly improved.
More recently, trials have been looking at whether or not you can go with a complete break in therapy without having to use a maintenance regimen. In general, we have two meta-analyses that have demonstrated that there's no adverse impact on survival and toxicity is better, although progression-free survival may be short.
As an example, in the FOCUS4-N Trial that had a variety of regimens, compared with using capecitabine alone or a complete stop after a fixed period of time, median progression-free survival was 1.9 months in the group that had a complete break in therapy. Parenthetically, it was 3.9 months in the group that underwent maintenance capecitabine, which isn't that much longer, and that group had a lot more toxicity. This, to me, is a discussion that's highly dependent on patient values and preferences. If you're going to do this, though, it's important that you make certain that the patient has responding disease and doesn't have a significant tumor burden in a critical site that if it grows during a complete break in therapy, the patient's going to be in trouble. And you have to maintain close surveillance to make sure you're right on top of things when the disease starts growing back, because then you reintroduce the drug at the time.
The benefit of intermittent therapy with irinotecan-based regimens is far less clear because there's really no cumulative dose affecting toxicity with those regimens. But they can beat up people, especially if you're on an EGFR-containing one. In my own practice, I treat patients as long as they're responding and tolerating therapy. But then when the tumor starts being stable, I stop and then I continue watching the patient and restart the regimen afterward.
Schlechter: I think both OPTIMOX and FOCUS4-N give us some guidance because they look broadly at this question of maintenance therapy and stopping therapy. But when you dig deep, there's a couple of nuances. Patients were seen for clinical evaluation monthly with every 8 weeks. I think that's really important. What I've learned in my own practice — and I'm sure you've seen this as well — is that patient selection is critical. You have to have a willing patient who's not going to worry about being off therapy. You need a patient with moderate-volume disease. Perineal disease is not a great place to stop. Bone disease is not a great place to stop, but I think for the right patient, the willing patient, the motivated patient, I think it's a good opportunity to focus on quality of life. You know that you've got the chemotherapy, and you can use it later, knowing that you don't lose anything as long as you watch closely.
Today we've had Dr Diane Savarese joining us discussing systemic therapy for advanced colorectal cancer. We discussed doublet therapy vs triplet therapy and combinations thereof. We talked about the critical value of boosting efficacy for patients where you're considering resection. Concerns were raised over EGFR inhibitors and resectable disease, and we talked about how EGFR inhibitors, panitumumab and cetuximab, have less benefit on the right-sided cancers, certainly in the first-line setting.
We talked about areas where we can use these regimens. We discussed that chemotherapy and these monoclonal antibodies are valuable agents to use, but they have a significant impact on quality of life and patient selection is really, really important — accounting for the risk profile of the patient as well as the values of the patient and what they want out of their treatment. That's, of course, always a very critical discussion.
Finally, we talked about stopping and starting chemotherapy. There is value in a break. Doctors need vacations and so do patients. I think it's an important lesson for all of us. Thank you for joining us. It's been a pleasure to hear your thoughts and your wisdom.
This is Dr Benjamin Schlechter for InDiscussion.
FOLFOXIRI Plus Bevacizumab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment of Patients With Metastatic Colorectal Cancer: Updated Overall Survival and Molecular Subgroup Analyses of the Open-Label, Phase 3 TRIBE Study
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Cite this: Systemic Therapy for Advanced Colorectal Cancer - Medscape - Oct 03, 2023.