Rethinking "More Is Better": Deescalating Cancer Care

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Jame Abraham, Enterprise Chair of the Department of Hematology and Medical Oncology. He was previously a guest on this podcast to discuss artificial intelligence in oncology and that episode is still available for you to listen to. He's here today to discuss deescalating care for patients with cancer. So, welcome back.

Jame Abraham, MD: Thank you, Dale. Thank you for having me again.

Dale Shepard, MD, PhD: Absolutely. Give me a little bit of an idea, what do you do here at Cleveland Clinic?

Jame Abraham, MD: As you mentioned, I'm the department chair or the enterprise chair for the hematology and oncology. I'm a breast cancer doctor. That's what I've been doing for the last more than 20 years or so.

Dale Shepard, MD, PhD: Excellent. We're going to talk about deescalating care, and I guess sort of as a beginning, there's a lot of people listening in, a lot of different backgrounds. If we're talking about deescalating care for cancer, give us a little bit of an idea how you think about it. What does that mean?

Jame Abraham, MD: That's a good question. Even I was thinking about that term this morning and I was thinking if deescalation is the proper term or optimizing the care, giving the right care or the optimal care for a patient with a specific diagnosis and specific, if I can use the term specific, biology. I've been doing breast cancer treatment or oncology care for more than 20 years. When I was reflecting on my journey and my career and how we've been taking care of patients in a day, as you know, a long time back, we consider all cancers as the same. If it's lung cancer, it's lung cancer. We gave the same chemo, carbotaxol. Every patient received carbotaxol. Or breast cancer, we gave the same treatment. Or lung.

Now, over the past 15, 20 years, with a better understanding of the subtypes of cancer, we know that not all lung cancers are the same, not all breast cancer is the same. So that's one. Number two, based upon that understanding, we have treatments which we can target or tailor for that particular diagnosis, and number three, to that particular patient. So I think there is huge paradigm shift in how we think about the cancer, the patient, the treatment happening in the past 10, 15 years.

Dale Shepard, MD, PhD: I guess in many ways we think about rare cancers, something like lung cancer or breast cancer, where there's a really large number of cases, we've sort of whittled down based on biology to a series of rare diseases in many cases.

Jame Abraham, MD: You're absolutely right. That's a really nice way of thinking. I know you said you read my op-ed in ASCO Post about forgotten lessons from South Africa. I think it's worthwhile for newer doctors to remember that when I was finishing my fellowship, we were really excited about doing stem cell transplant for breast cancer. That's based upon a fairly straightforward concept. There's a dose-response curve, and if you increase the dose, you'll get higher response. So, to cure the cancer, you just had to give more treatment, and that will wipe out the bone marrow. Then you give bone marrow or stem cells and rescue the marrow. So that is fairly straightforward and that was the norm.

Eventually we found out that that is not true. Randomized trials showed that strong. And then of course some of the falsified data came from South Africa led to that particular concept. So we came a long way from that concept of using a sledgehammer for cancer treatment.

Dale Shepard, MD, PhD: And then I guess the other thing is this is chemo when we're thinking more is better, but in many cases, if we're doing a DNA-directed therapy like an NTRK inhibitor or we're doing something that targets a receptor, we really have no idea necessarily that more is better.

Jame Abraham, MD: Absolutely. That's a really good point. There are studies looking at even the most commonly used immunotherapy, pembro, pembrolizumab, what's the optimal dose, and what's the duration of treatment? Do we need to give the treatment for a year? Or trastuzumab, Herceptin. There are studies which looked at six months versus a year. We just think based upon some of the assumptions made early on in the development of the drug, oh, a year is the right... this thing. But we don't know that for sure. There are studies from, as we were talking before, low and middle-income countries which are showing this equal efficacy for lower dose of certain immunotherapy, especially pembrolizumab, even shorter duration of treatments such as trastuzumab is as good as giving the dose what we use now.

Dale Shepard, MD, PhD: How do we get our colleagues to sort of see the world this way in terms of more isn't better? An example that comes to mind is adjuvant treatment for colon cancer. There are clearly people who just, if you think it is true, you have to give six months. There are people say you could probably give three months. There have been trials that each side will point to say, "See, clearly I'm right." How do we in all of these diseases get people to actually buy into this?

Jame Abraham, MD: That's the most important question. There are, let's just say, three major stakeholders in this conversation. One, the most important stakeholder is the patient, and of course, second, the investigators or the providers, and then if I can say the sponsors of the studies, the pharma plays a major role. So three major stakeholders in this conversation.

Now, what's happening? The patients are asking us, are you asking for more data for deescalation compared to escalation? Let me expand on that. I was at this meeting in San Antonio and there was a patient advocate really asked the entire audience or the investigators about some of these really pointed question. I'll give you an example. Of course, we all studied about radical mastectomy. Radical mastectomy, Halsted's approach, and the Hopkins team developed that 100 years back, and that's been the dogma. It took probably 60 years to break that dogma to say modify radical mastectomies.

Then it took probably 30 more years to change that from modify radical mastectomy to lumpectomy, and then sentinel node. So, patients are watching that we are taking so long to change this dogma, and now with an improved overall survival, they're asking us, how do we continue to focus on quality of life? Some of these questions you're asking, six months versus three months, I think survival is important, and quality of life is important. I think we really need to put the full picture together and continue to have this conversation.

Dale Shepard, MD, PhD: That plays in with a lot of the therapies, that whole quality of life part. If I have a discussion with a patient that has metastatic disease, I'm trying to control their tumor, make them feel better, make them live longer, and sometimes the higher doses, which, having being a phase one guy, we realize that a lot of those doses are what people tolerate, not necessarily what people need. So changing doses to make patients feel better is huge.

Jame Abraham, MD: That's a good point. Probably you can educate me. The historical concept of drug development is MTD.

Dale Shepard, MD, PhD: Right. It's not maximal biologic dose in some way, it's maximum tolerated dose.

Jame Abraham, MD: Even for that, we need a paradigm shift in thinking, right?

Dale Shepard, MD, PhD: Right, and again, as we think about immunotherapies and targeted therapies, do we really need as much as people can tolerate and then a little bit less? Probably not.

Jame Abraham, MD: Probably not, yeah. Shifting to quality of life, and of course, Dale, we've been doing this for some time, I think quality of life side effect management, side effect profile is really coming to the forefront in the conversation. It's really fascinating. I'm so privileged to be taking care of patients with breast cancer. In the past, let's just say somebody has metastatic breast cancer, a small lesion in the lung, ER-positive, we are starting the patient on chemo and a Taxol or capecitabine or something, but now that's completely shifted to a pill in a CDK4/6 or antiestrogen treatment or PI3K inhibitor. We have so many choices now where patient can maintain a quality of life.

Dale Shepard, MD, PhD: What do conversations look like if you are seeing a patient, you talk about, well, "Maybe you're not tolerating this so well. Instead of switching to a drug, maybe we reduce the dose"? What kind of discomfort do you see with patients, or do they welcome that change? What does that look like?

Jame Abraham, MD: That individual, but one of the question I hear is, let's just say we have a patient with metastatic breast cancer and then when I say, "Hey, you don't need chemo. You can be treated with an antiestrogen and a CDK4/6, or a PI3K or ESR1 mutation agent, the patient will ask me again, "Hey, are you sure? I'm willing to take chemo. I'm fine," and I said, "No, you don't need chemo, and these medicines are as good or even better, not even, definitely better than chemo." And then, as you said, we can optimize the dose based upon their side effects. They can clearly reduce the dose because it's different, and of course you're a pharmacogenomic guy and it's really different for different people how much they can tolerate.

Dale Shepard, MD, PhD: Last time we had the opportunity to talk to you, we talked about AI. How much do you think biomarkers, either blood-based biomarkers, there's this big craze now with circulating tumor DNA and using AI, how much do you think that's going to affect how we can more effectively optimize therapies, do dose deescalations, find populations that don't need as much drug, things like that?

Jame Abraham, MD: I think it'll tremendously influence, especially with amount of genomic information we get and how do we dissect that information, and what does that mean. I think AI will definitely help. I'll give you a simple example. It's not a clear AI, but OpenEvidence. OpenEvidence is an AI-based platform which helps doctors to filter through information. Let's just say a doctor is getting this complicated genomic information, probably has tough time to find what's the next treatment, what's the best, let's just say, clinical trials based upon that genetic mutation. That platform or similar platforms will allow physicians to guide to the right place. I'm not saying they have the perfect answer, but they'll help people to go to the right place.

Similar tools which are practical enough for clinicians will continue to evolve. That's one part. The second part is, of course, genomic information-based treatment eventually will be guided by AI power, definitely. Of course, that's your specialty. Thirdly, as you know really well, the AlphaFold and some of these Google's extremely powerful protein synthesis tools are really changing how the drug discovery or drug development is happening. So it's an exciting time.

Dale Shepard, MD, PhD: It is an exciting time. You talked about dose escalation with that whole transplant theme with breast cancer, more is better. That clearly didn't work so well. Can you think of examples of, we think about escalation or deescalation rather as being something that's useful, can you think of examples of where it just hasn't worked?

Jame Abraham, MD: There are some studies, if you look at the paclitaxel story, the Taxol story, when the Taxol came out, we all thought at that time we had only Taxol and we were trying to give it every three weeks or weekly or continuous infusion. That's a story where some of this changing the dose didn't really work out. Initially in 1990s, they were trying to give Taxol for continuous infusion for 24 hours or even longer time, and if you continuously expose the tumor to the cytotoxic agent, potentially there'll be more cell kill. That didn't work out. So not all approaches we try will work out, but I think we need to continue to look at those options and see if that can improve survival and maintain a quality of life.

Dale Shepard, MD, PhD: You mentioned three stakeholders in terms of some of these trials. Ultimately, one of the stakeholders being companies that are trying to get drugs approved, and there's a lot of time and energy and money that goes into that process. How easy do you think it's going to be to do formal deescalation studies where ultimately a company that's a sponsor is wanting to sell drug, they've already put a lot of money into that? Is this going to fall to co-op groups, do you think, to show this in a meaningful way or how do you think we're going to actually get the studies done that show that deescalation strategies work?

Jame Abraham, MD: Oh, really important and good question. If you look at, there are three or four forces will influence that. One, the most important is the patient voice. The patient voice will force that. Second, the payers or the resource. When I say that, I'm not just talking about the insurance companies, I'm talking about countries or health systems, health systems like NHS, or countries where the resources are limited, countries like India where you may not be able to give that full dose for a year or two years. So the patients, I think the resources, the insurance and the countries or the systems will force that conversation.

And then it's really important for the investigators or doctors like you and me to continue to have this conversation so that the patient voice is not lost in that conversation. I'm not saying the industry won't make it happen by themselves, but as you are alluding, there is a conflict of interest in that conversation. That's true, as you know really well, about biomarker selection-based treatment. In general, a company with the drug wants to give that to the full population there. Subselection is not exactly a good strategy for them.

Dale Shepard, MD, PhD: As you look within breast cancer, you think about either optimizing based on a marker, optimizing based on doses. Where's the greatest need right now? Is it in adjuvant setting, neoadjuvant? What do you think is one of the bigger unmet needs?

Jame Abraham, MD: A triple negative is still an unmet need and we are making huge strides with the neoadjuvant immunotherapy. Of course, it's almost 60% complete response, more than 60% complete response we are seeing with immunotherapy-based regimen, but in metastatic triple-negative, potentially we can use antibody drug conjugate, we can use immunotherapy if it's PD-L1 positive or PARP inhibitors, but still there's a huge unmet need.

Dale, as you know well, and we are so happy with the progress we are making, but still we have huge and a long way to go, even ER-positive, which is 60% of patients. Once the tumor become resistant to some of the antiestrogen treatment, CDK4/6, and then we are moving into antibody drug conjugate, we continues to need newer treatments to treat our patients. So we still have long way to go in all subtype, including HER2-positive.

Dale Shepard, MD, PhD: So lots of progress over the years, lots of work still to be done.

Jame Abraham, MD: Absolutely.

Dale Shepard, MD, PhD: Appreciate you being here and giving us your insights.

Jame Abraham, MD: Thank you, Dale. Thank you for having me again. And thank you for what you do. You're educating caregivers and the doctors, the care team, and of course the patient. Thank you for what you do.

Dale Shepard, MD, PhD: Absolutely.  To make a direct online referral to our Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.  

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