Dr. Shaalan Beg and Dr. Arjun Gupta discuss the rationale behind treatment breaks and assess the pros and cons based on feedback and data from patients with advanced-stage gastrointestinal cancers.

TRANSCRIPT

Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center in Dallas and senior advisor for clinical research at the National Cancer Institute. I'll be your guest host for the podcast today.

On today's episode, we'll be discussing treatment holidays in GI cancers. Treatment holidays, also known as drug holidays, are increasingly being discussed in clinical practice and involve voluntarily halting treatment for a duration determined by a health care provider if believed to be beneficial for a patient's well-being. We'll address the rationale behind treatment holidays and explore their potential risks and benefits. Joining me for this discussion is Dr. Arjun Gupta, a GI medical oncologist and health services researcher at the University of Minnesota. Dr. Gupta's research on treatment-related time toxicity has explored the benefits of taking a break from treatment.

Our full disclosures are available in the transcript of this episode.

Arjun, it's great to have you on the podcast today.

Dr. Arjun Gupta: Thanks, Shaalan. It's a joy to be here.

Dr. Shaalan Beg: Your research at the intersection of oncology, supportive care, and care delivery is extremely interesting and important in today's day and age. And you've done extensive work on the concept of time toxicity in cancer treatment. So as we think about these discussions in the clinic on treatment holidays and we talk about risks and benefits, I was hoping that you could help explain the concept of time toxicity in cancer treatment and what our listeners should remember from this.

Dr. Arjun Gupta: Sure. So time toxicity is simply the time commitments that cancer care imposes on people with cancer and their loved ones, and the burden that comes along with these commitments. When we specifically think about time toxicity associated with a particular cancer treatment, such as chemotherapy, it's the time costs of pursuing, receiving, and recovering from cancer treatment. Now, we have to acknowledge that much of cancer care is essential. We need blood tests to monitor organ function, we need chemo to shrink tumors, and we need a caring oncologist to break bad news. But we have to remember that oncology care is delivered in an imperfect world. Appointments that should take 10 minutes can take 5 hours. People can have uncoordinated appointments, so they're coming to the clinic 3, 4, 5 times a week. And this affects, of course, not only the patient themselves but also their informal care partners and the entire network around them. And this cancer care can completely consume people's lives, leaving no time for rest, recovery, or pursuing joyful activities.

We interviewed patients and care partners in some qualitative work, and this was specifically people with advanced-stage gastrointestinal cancers. And we asked them what cancer care was like, and some of the words will shock you. People said things like, “It's like being on a leash.” “My life is like being on an extended COVID lockdown.” “Cancer is a full-time job.” A very experienced oncologist said, “It's like being on call. You may or not get called into the hospital, but you need to always be available.” And so this concept of time toxicity really applies to all people with cancer, but perhaps most so for people with advanced-stage, incurable cancer, when time is limited and when treatment regimens are perhaps not offering massive survival benefits. And in some cases, the time costs of pursuing the treatment can even overtake the very marginal survival benefit offered by the treatment.

Dr. Shaalan Beg: This is particularly relevant for gastrointestinal cancers that, even in the world of advanced cancers, are highly burdensome in terms of their symptoms and the concept of being on call, whether you're a patient or a caregiver, and the burden that it has, I think will resonate with a lot of us, that it's always in the back of our mind on what if X, Y or Z were to happen? In the FOCUS4-N trial, a randomized trial from the UK, investigators assessed whether taking a treatment holiday for maintenance therapy for metastatic colorectal cancer would have a detrimental effect on progression free survival, overall survival, tolerability and toxicity. It looks like the study found that these decisions regarding maintenance therapy should be individualized, but there were not major differences in outcome. Can you comment on this and what applications that has for us in the clinic?

Dr. Arjun Gupta: Sure. But before diving into the FOCUS4-N clinical trial, I just wanted to share a story from the clinic yesterday. It happened in my clinic yesterday, but I'm sure it happens to thousands of patients across the world every single day. So it was the first visit for a patient with stage 4 colon cancer, and they had polymetastatic disease with disease in the lungs and the liver, no actionable biomarkers, and so very likely to be incurable. And so we discussed the usual port and palliative care appointments and chemotherapy backbone, and doing this every 2 weeks, and then doing scans after 4 to 6 doses of chemo to see how the cancer has responded. And then the patient looks up and asks that question, “Okay. So when does this end? When are we done? Do I need to do this forever and the rest of my life?” These are just such innocent and hopeful questions, because the truth is, there is no established end date. But I shared this story that right off the bat, people are looking for breaks. They've not even started chemo, they've not experienced physical or financial or time toxicity, but just psychologically, being on chemo long-term or forever is a very, very hard adjustment.

And so it's in this context that we should look at the FOCUS4-N clinical trial, which was a sub- study of a larger umbrella trial investigating whether continuing on maintenance chemo with oral capecitabine versus taking a treatment break from chemo affected the progression-free survival in people with metastatic colorectal cancer who had disease control after 4 to 6 months of upfront chemotherapy. So they randomized approximately 250 people. These people had largely been treated with FOLFOX or FOLFIRI. Most did not receive a biologic, and approximately half had partial response and half had stable disease. And then they did scans on these patients every two months or so. And the primary endpoint was progression free survival. The median PFS was approximately 4 months in the capecitabine arm and 2 months in the no treatment arm. Of course, as expected, side effects were higher in the capecitabine arm. But impressively, the overall survival was not different between these two arms. So what we're seeing here is that after this period of 4 to 6 months of intensive chemo, if we take a chemo break versus we get some oral chemotherapy, it may affect how quickly the cancer grows on scans, but it maybe does not affect how long patients live.

Now, how do these data apply for an individual patient? Now, these are incredibly nuanced and personal decisions and patients can and should choose what aligns best with their values. In some work done by Dr. Mike Brundage and colleagues in Canada, they asked 100 people with advanced cancer to consider hypothetical scenarios where a new treatment did not increase the overall survival, but potentially increased the progression free survival at the cost of some physical and other toxicities. And then they asked patients if and what PFS thresholds they would accept for this treatment. And around half of patients said no matter how big the PFS is, we do not want to accept the treatment because it causes some toxicity if I'm not going to live longer. Around a quarter of patients said that if the drug elongated progression free survival by three to six months, I would take it, because that's valuable to me even if I don't live longer. But surprisingly, 1 in 6 patients said that they would accept a treatment with no PFS benefit and no overall survival benefit, even at the cost of side effects. And there was a spectrum of reasons for these preferences that they maybe had the battle narrative that “I want to be a fighter, and I don't want to have any regrets,” just showing how complex people's attitudes and values can be. So the point is that continuing on maintenance treatment versus not doing it is not wrong. The point is we often don't even have these data to offer treatment breaks to patients so that they can make decisions that align with their goals.

So I think that's the biggest takeaway from the FOCUS4-N trial for me is that we have some hard data now to guide patients [FOCUS4-N Editorial]. Now, strictly speaking, when I'm talking to a patient about these data, doing oral capecitabine in 3-week cycles may not feel like much. It's perhaps a visit every 3 weeks for blood work and for meeting someone from the oncology team. There are no IV drugs given. If one does well, this might literally be one visit every 3 weeks. But we have to consider that things rarely go as smoothly as we plan them to. For someone living 100 miles away and having diarrhea and needing IV fluids, they may require 3 to 4 clinic visits for labs and monitoring.

In the FOCUS4-N trial, 50% of patients on capecitabine had at least one treatment delay, denoting some toxicity. In a different but similar CAIRO3 clinical trial that tested capecitabine and bevacizumab, 10% of patients had to discontinue treatment due to toxicity. And so it's important to remember that what might seem a simple and low burden to us may be very burdensome to patients. In some work that we've done ourselves [published in The Oncologist], even a single simple appointment to a clinic, such as a lab test, often ends up taking patients hours and hours. So I think it's all of this that we have to consider when we present these data to patients.

Dr. Shaalan Beg: You've talked about the FOCUS4-N trial, you mentioned the CAIRO3 study as well. How do you see this playing in the clinic? Somebody may be looking to attend a child's wedding or a notable birthday or a trip with the family, and you have the data from these trials supporting you. What are the patient factors in terms of their disease factors, patient factors that you think of when you recommend such a treatment break to a patient? Or, let me flip that over. Who would be a patient that you would be uncomfortable offering a treatment break for with metastatic colorectal cancer?

Dr. Arjun Gupta: Yes, I think disease characteristics are a crucial consideration when we consider who we're even offering these treatment breaks to. I think, number one, is the overall disease burden, and if there's any critical visceral disease and how that's responded and how much it's responded to the upfront chemotherapy induction. I think patients where we're worried about having several sites of bulky disease, some that have not responded as well, I think we have to be very, very careful considering complete chemotherapy breaks. In the FOCUS4-N trial, in subgroup analysis, patients who had stable disease tended to not benefit as much from the chemotherapy break, perhaps indicating that it's really people whose disease is responding, who are doing well, who don't have as much disease burden, who may be better served by these treatment breaks.

Dr. Shaalan Beg: Fantastic. I think that provides very good direction for our listeners on how they can apply the results of these trials in their clinic.

So we've talked about treatment breaks as a way to give people their time back and to reduce time toxicity. What are other treatment strategies that you have seen deployed to reduce the burden of receiving cancer treatments in general?

Dr. Arjun Gupta: You specifically asked about treatment strategies, so I'll start with that before moving to more broad interventions. We actually interviewed patients and care partners to ask them this question, and one of the things that they said was having prospective information from their oncology care team just about what my expected burden was going to be. So I think people recognize that they need oncology care and the clinicians are trying to help them and it's a broken system, but just knowing that 1 in 4 days will be spent with health care contact or not, or you will spend two hours arguing on the phone with a payer, for example, preparing and supporting people for these burdens is very important. There are obviously some alternative treatment schedules. Certain chemotherapies can be given less frequently now. So if you look at cetuximab in GI cancers, for example, when the initial trials were done, it was given every week, but now we more and more use it every two weeks. And it might not seem like much, but it can open up an entire week for a patient when they can think that I don't need to go in this week at all. So these are just some minor adjustments that we can make in the clinic.

But patients often highlight things that may perhaps not be in the direct control of the oncologist, but in the direct control of us as an oncology community. And perhaps the most frequently cited suggestion was having more care coordination and navigation services. So patients really requested more flexibility in the site of care: “Can I come closer to home?’’ In the timing of their care, ‘’Can I come in at 2:00 PM after I get childcare instead of coming in at 9:00 AM?” They really requested cluster scheduling or having appointments on the same day, if possible, instead of taking up Monday, Tuesday, Wednesday, Thursday, coming in so many times. And all of this could potentially be achieved by having a designated care coordinator, someone working directly with the patient and their care partner. And then some patients also highlighted the benefits of telemedicine and home-based care, where they were able to be home more.

But we have to also recognize that those things are not universally good and often can increase burdens on the patients and care partners. Also, I wanted to highlight some feedback we received from oncology clinicians. We asked a variety of oncology clinicians, including nurses, APPs, physicians, schedulers, and social workers, what they thought were the causes of patients’ time burden. You'll be surprised to hear that when they started talking about patients’ time burdens, they slowly started to talk about their own time burdens. And they said, ‘‘We really want to help people, but we're just doing prior authorization and spending hours on the electronic medical record. And please fix my own time toxicity, and I will fix the patients’ time toxicity,” which I thought was very profound because I think everybody who goes into medicine goes into it for the right reasons, and we end up not providing perfect care, not because of us, but because of the system. I take this as a very, very positive sign and as a hope for change.

Dr. Shaalan Beg: What inspired you to focus on this topic and your research?

Dr. Arjun Gupta: So I personally just hate waiting at the doctor’s office. But yes, it's also been wise mentors, including you, Shaalan, during residency and fellowship, who always told me to keep my ear to the ground and listen to patients. And in full disclosure, time toxicity, and what we've done with it recently, it's nothing new. It's been around for decades. And I think our research group has just sort of named it and shamed it, and now more and more people are starting to think about it.

But I can point to two specific instances that I think of. One was when I was starting fellowship in 2018, I read a piece by Dr. Karen Daily in the Journal of Clinical Oncology, where she quoted Henry Thoreau and said, “The price of anything is the amount of life, or time, that you exchange for it.” And it really struck a chord with me, entering the oncology discipline and seeing what people with cancer go through.

And then the second instance is, I remember my granddad, who was perhaps the most formative person in my life. We were very, very close. And when I was about to enter medical school, he was undergoing chemotherapy for lymphoma. The image that's imprinted in my head is of him putting ketchup on gulab jamun. And I can see Shaalan salivating. But for the listeners who may not know, gulab jamun is an Indian sweet made out of milk, flour, sugar, ghee, molded into balls, deep fried and then served in sugar syrup. And my granddad could not taste anything. He could not taste gulab jamun. All he could taste was ketchup. And so he would put ketchup on everything. And at his oncologist visits when I would accompany him, they would discuss the good news about the cancer shrinking and there being a response, and he was happy, but he could just not taste his gulab jamuns. And it made me realize very early on that the tumor is not the only target.

Dr. Shaalan Beg: What a wonderful story. I think those are really hard to measure, quantify, and when patients do bring those stories into the clinic, I think you realize that you have a very special connection with those patients as well, and it does help us as clinicians give personalized advice. So thanks for sharing.

Arjun, thanks for sharing your valuable insights with us on the ASCO Daily News Podcast today.

Dr. Arjun Gupta: Thanks so much for having me, Shaalan.

Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the studies discussed today in the transcript of the episode. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Find out more about today’s speakers:

Dr. Arjun Gupta

@guptaarjun90

Dr. Gupta’s Research on Time Toxicity:

· The Time Toxicity of Cancer Treatment, JCO

· Consuming Patients’ Days: Time Spent on Ambulatory Appointments by People With Cancer, The Oncologist

· Evaluating the Time Toxicity of Cancer Treatment in the CCTG CO.17 Trial, JCO OP

· Patients’ considerations of time toxicity when assessing cancer treatments with marginal benefit, The Oncologist

· Health Care Contact Days Experienced by Decedents With Advanced GI Cancer, JCO OP

· Health Care Contact Days Among Older Cancer Survivors, JCO OP

Dr. Shaalan Beg

@ShaalanBeg