Let’s discuss the whole concept of maintenance therapy. Throughout the years, a number of studies consistently show that giving chemotherapy until progression may not be the wisest decision, at least intensive chemotherapy. What do the data tell us? What do you do typically for your patients? How long do you treat them, and what type of maintenance therapy would you consider? Do you ever consider chemotherapy-free intervals, and what does that mean?

 This is something we grapple within the clinic, even today, despite having all of this evidence. The basic principle here that we follow is that we know patients will reach their point of maximum response with first-line chemotherapy, generally by about month 3 to month 4. After that, the responses tend to level off.

At the same time, as you go past month 4 on your frontline combination chemotherapy, the toxicity can build up, specifically for the oxaliplatin-based regimens. We can see worsening neuropathy, which in some cases can be disabling and cause quality-of-life issues. There’s no evidence that continuing a combination chemotherapy approach past that initial point of maximum response improves overall survival.

Right around month 4, we take a step back, and we say, “How are you doing? How are you feeling? What’s the scan showing?” If a patient has achieved some degree of benefit from that regimen, we oftentimes are thinking about peeling off that aspect of chemotherapy that’s causing the patient the greatest quality-of-life issues. If a patient is receiving oxaliplatin, that would be something that is routinely discontinued, right around month 4. Rarely do I continue it past that point, though in some rare cases I might consider it.

But additionally, there are some patients who just need a break period, from everything. Maybe it’s the travel to the cancer center, the emotional demands of coming in, they want to go on vacation, or be with family; it is also OK for that patient to take a chemotherapy holiday and take a break. It does mean that that patient is more likely to start second-line chemotherapy sooner. On the other hand, there would not be a major impact on overall survival for a person to take a break or a holiday, for a period of time.

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Recommendations regarding the selection, initiation, and length of maintenance therapy to help manage cases of metastatic colon cancer.

Maintenance Therapy for Metastatic CRC

I want to go back to your discussion about intensive therapy. Are younger patients the right patients who we need to intensify therapy?

 That’s a very interesting observation. With BRAF, for example, it’s a group analysis of TRIBE. We thought that BRAF would benefit more from more intensive therapy, but when you look at the subgroup analysis of TRIBE2, it doesn’t pan out much when you increase the number of patients.

 I have to chime in, TRIBE2 was not powered for BRAF.

 None of these subgroups was powered for BRAF, but the effect size that you see does not translate across the board. If somebody has poor biology, BRAF is an exception because we know these patients tend to be chemotherapy-refractory. All you’re doing with triplet cytotoxic is just giving another chemotherapy drug. It may not be true for young patients, but the data show that younger individuals may have poorer outcomes compared with garden variety colon cancer.

Before deciding, I usually look at disease characteristics, rather than age, to decide whether I need to give this. A patient who has small lung disease, even if they are young, may not be appropriate candidates for a triplet cytotoxic coming from shared decision-making principles. On the other hand, for somebody with peritoneal carcinomatosis, where we know that it did progress and it’s hard to predict that they would get into trouble, those are patients I like to be really aggressive with up front. Once they get into the cycle of malignant bowel obstructions, it’s difficult to reverse it.

The liver is a different group. In the resectable population, we want to be careful because even though there was an increase in response rate, the resection rates were not high. Our surgeons are afraid of steatohepatitis that comes from irinotecan. It’s more than just 1 thing. Younger individuals are more likely to get a more aggressive treatment.

Is that true for your patients, Joleen? You see quite a few in your clinic as well.

 I have been seeing an increase in young adults with colorectal cancer. I try to offer them more aggressive therapy because ihey’re more likely to tolerate it. They’re more likely to have young children. They want to maximize the amount of time that they have. I do try to get my younger patients to be a little more on the aggressive side, in the hope that we can control their disease better for a longer period of time.

The rationale for treating select patients with metastatic colorectal cancer with intensive therapy in the first-line setting vs waiting until disease progression.

Applying Aggressive Therapy to Treat mCRC Up Front

Dr Eng has near and dear to her heart a subject that’s becoming a tragedy in cancer overall but more so in colorectal cancer than any other cancer: seeing these incredibly young patients presenting with colon cancer. It’s becoming very difficult to understand why. Can you discuss what is going on with this? What’s happening in our world of colorectal cancer?

 I wish we knew the exact etiology to account for this, but the data estimate a 90% to 124% increased risk of colorectal cancer vs 2010. Many individuals, like me, are trying to investigate what’s to account for this. There are multiple factors that people are looking at that have been reported, but there are a lot more data that we need to determine.

It’s important that these patients are recognized. It’s wonderful that the screening rate has been reduced to 45 years old, but that’s not going to help our very young patients. I want to remind people that for the majority of these patients, it’s just sporadic colorectal cancer. These are not inherited forms of colorectal cancer. Many of these patients have had symptoms, if you ask, going back 6 months to 2 years ago, where they noted a change in bowel habits. Some may have gone to the primary care doctor, but then their primary care doctor thought that they looked too well so there was no way they had colorectal cancer. And they’re often misdiagnosed, or often the patients themselves attribute it to hemorrhoids or some other IBD [inflammatory bowel disease] etiology to account for it.

Many of us are trying to determine why this is happening, but it is alarming and concerning. March is colorectal cancer awareness month. These young adults need multiple support factors, and you need to inquire about fertility before starting therapies as well as life planning and advanced directives, because many of them present with stage IV disease. You need to talk to them about what their job is, job security, financial security, etc. Always refer them to genetics when appropriate because many of them actually may have had some family history. They just didn’t know about it until they were diagnosed.

I do want to highlight we do have a young adult cancer program at Vanderbilt-Ingram Cancer Center. I’m delighted to serve as the director for that.

Cathy Eng, MD, FACP, FASCO, of Vanderbilt-Ingram Cancer Center reacts to the increasing rate of colorectal cancer among the younger population and highlights topics that apply specifically to counseling younger patients.

Colorectal Cancer in a Younger Population

When you’re sitting with a patient, and we have moved more toward the shared decision-making, what things get discussed with the patient to help them make the right decision as you’re navigating them through the treatment options?

 It’s always a risk-vs-benefit discussion. With FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan]–bevacizumab] for first line, it’s hard to argue with 2 randomized phase 3 trials showing a 4-month overall survival benefit. If it’s purely the palliative situation, we don’t need conversion, and we have a patient who says they’re concerned about adverse effects and would rather have fewer adverse effects and more interaction with family or at their job than having more adverse effects and potentially other outcomes. Those are things you always have to take into consideration. Each step of the way, we look at the risks and the benefits. When we get into second-line therapy, usually patients are still feeling good, and you can get a doublet cytotoxic and biologic in. When we start to get to third- and fourth-line therapy, that’s when we need to take a deep breath and ask, “Is this worth to continue going forward for minimal response and a small amount of survival benefit for some patients, but definitely with some toxicities?” In addition, asking what their goal is in the time they have. Each patient is different. Some patients want to try everything and push, and some opt for more comfort and quality of life. It’s all how they want to spend their time.

Every line of treatment, with every visit, you’re having that discussion with the patient.

John, do you want to add anything to that?

 It’s important to sit down with your patient on day 1 and then continue to have discussions about what’s important to that person, what they value, and what they want to be doing with their time. You must understand that, unfortunately, in most cases, we can’t cure patients with metastatic disease. We are looking to give people as great a quality of life as possible. In some cases, length of life is the primary consideration. In other cases, the primary consideration is minimizing the risk of needing to come in more frequently for IV [intravenous] fluids and minimizing toxicity related to treatments. Most preferences can change over time. We’re incorporating those discussions into our treatment decision-making. By doing that, we’re giving our patients the best care possible.

An overview of topics that oncologists should counsel patients on when working with them to select therapy to treat metastatic colon cancer.

Optimizing mCRC Treatment: Decision-Making With Patients

® titled “Personalized Approaches to Treatment of Metastatic Colorectal Cancer.” The past 12 months have been transformative in gastrointestinal oncology. Practice-changing data continue to emerge, particularly surrounding more personalized management of metastatic colorectal cancer. These are exciting times in the treatment of metastatic colorectal cancer. My name is Tony Bekaii-Saab. I’m from the Mayo Clinic in Phoenix, Arizona. Joining me in this discussion are John Strickler from the Duke Cancer Institute in Durham, North Carolina; Kanwal Raghav from The University of Texas MD Anderson Cancer Center in Houston, Texas; Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee; and Joleen Hubbard from the Mayo Clinic in freezing Rochester, Minnesota.

In today’s discussion, my colleagues and I will discuss recent data from the key clinical trials and implications for how metastatic colorectal cancer should be treated in 2021. Let’s start by discussing your approach to the initial assessment of a patient with newly diagnosed metastatic colorectal cancer. How do you decide on choices of frontline therapy? What factors or characteristics help you decide on treatment?

 The first-line chemotherapy for colorectal cancer has evolved over the past few years. Overall new patient tumor characteristics need to be balanced before I make those decisions at least for current management. In totality, molecular profiling and tumor characteristics trump most everything. We try to do next-generation sequencing and molecular profiling up front for our patients with colorectal cancer. Then there are these buckets that you recognize, and that’s how treatment follows. The most important thing is…testing where immunotherapy becomes a good first-line option. Beyond that group, if you have a…population, then your treatments are restricted to cytotoxics and anti-VEGF agents: Bevacizumab–FOLFOX [5-fluorouracil, leucovorin, oxaliplatin], bevacizumab–FOLFIRI [5-fluorouracil, leucovorin, irinotecan hydrochloride], and bevacizumab–FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] are 3 good options. That depends on other patient characteristics. I have become a big fan of using triplet cytotoxics after the positive data from TRIBE and TRIBE2 studies, but only for patients who are robust enough...

The choice between FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] and FOLFIRI [5-fluorouracil, leucovorin, irinotecan hydrochloride] is mostly based on discussions with patients about hair loss, toxicities such as neuropathy, and certain comorbidities that could restrict the use of 1 agent over the other. Then comes the question of anti-EGFR drugs, which are the 

 wild-type group. In this group, we like to identify 2 separate groups, the BRAF and the…separately because those preferably should move toward clinical trials as early as possible. But for the remaining ones, if you’re left-sided, we try to make anti-EGFR up front if possible. These things are also dependent on how quickly we need to start treatment and how quickly we’re going to get results. If you’re a right-sided tumor, then we go more along the lines of…patients.

 You said you’re moving more toward 3-drug regimens. How do you decide on a left-sided patient who has all the good molecular genetic markers for a triplet vs an EGFR inhibitor?

 On the question of a triplet cytotoxic regimen like FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan], the favorable factor is usually bevacizumab. FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan], even though there are some data out for its feasibility, becomes extremely toxic. If you have appropriately selected your population for an anti-EGFR, if they are distal left-sided, 

 negative, then the response rates, with Cytoxan in combination with a double agent should be big enough not to warrant the extra toxicity of FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan].

FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] is best in really young individuals, possibly 

-mutant patients, or those who have an aggressive disease like peritoneal carcinomatosis. That’s where I generally use it in combination with an anti-VEGF like bevacizumab.

 Regarding the FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] combination with anti-EGFR therapy, the VOLFI trial was a small, phase 2 study, less than 100 patients. Some individuals like to consider utilizing it, but they did have 25% grade 3 or 4 diarrhea. That’s important to keep in mind. I agree with Kanwal on this. There’s a very select population that we can potentially use that for. I also tend to use bevacizumab in that setting much more with anti-EGFR in a triplet.

 Would you ever use FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] and an EGFR inhibitor? Is there any setting where you think this is a reasonable option?

 Given the high response rates, if you have a young patient with good performance status, and you need a Hail Mary to try to convert them from unresectable to resectable, that might be 1 situation for someone with a left-sided tumor where I’d consider using that. Otherwise, based on the toxicities and the lack of phase 3 data, I’m not using it routinely in a first-line setting.

 A triplet FOLFOXIRI [5-fluorouracil, leucovorin, oxaliplatin, irinotecan] is appropriate in some cases of robust, fit patients who are wanting to be aggressive. The preferred partner of TRIBE and TRIBE2 studies is bevacizumab, but in most cases, that regimen is a bit much for the average person coming in, so we need to be thoughtful about who we’re giving that to and just make sure that we’re matching the right treatments to the right person.

Experts in gastrointestinal oncology highlight their approaches to assessing patients with newly diagnosed metastatic colorectal cancer and explain the variables that factor into first-line treatment decisions.

John H. Strickler, MD, Duke Cancer Institute

Articles

Maintenance Therapy for Metastatic CRC

Applying Aggressive Therapy to Treat mCRC Up Front

Colorectal Cancer in a Younger Population

Optimizing mCRC Treatment: Decision-Making With Patients

Initial Strategies for Assessing and Treating mCRC