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Ursula A. Matulonis, MD: Hello. I'm Dr Ursula Matulonis, and welcome to season 1 of the Medscape InDiscussion Endometrial Cancer podcast series. Today we'll discuss survivorship issues in endometrial cancer, common symptoms, sexual dysfunction, and ways to improve quality of life. First, I'd like to introduce my wonderful and internationally recognized guest, colleague and friend, Dr Alexi Wright. Dr Wright is an associate professor of medicine at Harvard Medical School in Boston, Massachusetts, and the director of the gynecologic oncology outcomes research at the Dana-Farber Cancer Institute. She's a practicing medical oncologist who specializes in gynecologic oncology and health outcomes research. Alexi, welcome to the Medscape InDiscussion Endometrial Cancer podcast. It's great to have you here to talk about these important survivorship issues for our patients with endometrial cancer.
Alexi A. Wright, MD, MPH: Thank you so much, Ursula. It's such a pleasure to be here. You are the person who inspired me to focus on gynecologic cancer. I'm really happy to be here with you.
Matulonis: Your research has focused on a number of different topics, including quality of life for our patients with gynecologic cancers, the role of exercise in survivorship, healthcare disparities and others. I'm going to start by asking you about the most important survivorship issues that our patients with endometrial cancer face today, such as fatigue, neuropathy, and sexual dysfunction as well as other symptoms that you have researched. Let's start with fatigue. Patients certainly experience this during treatment but many patients say it lasts longer than that.
Wright: You could not be more right. Fatigue is one of the most common and distressing symptoms that people with cancer experience, and it oftentimes actually persists for years after treatment ends. We recently followed a large group of women who had endometrial cancers and we found that nearly 40% of women had clinically significant persistent fatigue 1 year after they had completed treatment. These are patients who went through surgery, radiation, were done with treatment, the cancer hadn't come back, and they were still disabled by their fatigue. Before this study, I have to admit, I thought after patients recovered from the physical and emotional aftermath of treatment, fatigue would fade with time. But for a substantial proportion of patients, that simply isn't true.
Matulonis: That's pretty significant. What do we do about that? Do you have any suggestions or recommendations for our patients who are experiencing fatigue during treatment and after treatment as well.
Wright: Absolutely. I first rule out common medical causes for fatigue, things like thyroid disorders, anemia, or depression. Usually those things aren't to blame. Once they are ruled out, I encourage patients to exercise or consider cognitive-behavioral therapy (CBT). There was a large meta-analysis published in JAMA Oncology a few years ago that looked at the evidence for pharmacologic strategies, exercise, and CBT. It's really clear that exercise and psychological interventions are far better at treating fatigue than medications. It's actually similar for sleep. A lot of our patients complain of insomnia or difficulty sleeping. For a long time, we gave them sleep aids, but we're finding more and more that CBT helps more than pills.
Matulonis: How easy is it for patients to find out about CBT in their community?
Wright: There's a number of barriers. Some patients don't want to see a therapist, but there are also issues in the workforce. Many therapists either are unavailable or don't practice CBT. There's been a call to increase the number of CBT clinicians practicing, particularly for cancer patients. It's hard to find therapists, but there are actually some commercially available companies and apps that you can access, and CBT seems to really help, particularly with sleep and also fatigue.
Matulonis: You've done a lot of research, but you've also done some work using psychological interventions to reduce fatigue. Can you tell us a little bit about that?
Wright: Yes. We recently piloted a psychological intervention that's a CBT variant called Acceptance and Commitment Therapy to help treat fatigue in patients on poly (ADP-ribose) polymerase (PARP) inhibitors. We did it in patients with PARP inhibitors, but the same principle should apply to patients with endometrial cancers who, for example, are on pembrolizumab or lenvatinib. Both can cause a lot of fatigue. Patients participated in six sessions with master's level–trained psychologists, this has also been done with social workers who helped them use a combination of acceptance, mindfulness, and behavior-change strategies to help patients cope with their fatigue. That's particularly important when people have to stay on treatment for months or years. The idea really was to shift how patients experience and cope with fatigue to help spare them from spending their precious energy on trying to control it or avoid it or to focus on difficult thoughts and beliefs about fatigue. A lot of times people worry that the fatigue may signify that they're recurring or something's wrong with them and dedicate a lot of energy and rumination to that.
What we found was that this six-session brief intervention significantly reduced patient's levels of fatigue and also the ways that fatigue interfere with their lives. Surprisingly, we found that the patients who received the intervention had fewer dose reductions in their PARP inhibitors and also fewer delays. So now, we're testing this in a larger, more diverse group of patients to see if it helps have lower levels of fatigue and also be more adherent to treatment, which can be a big issue.
Matulonis: I've definitely had a few patients on your trials who've gone through that program and definitely benefited. It's great that you're expanding to more patients. Tell us about prevention. Are there ways to prevent fatigue in our patients?
Wright: For a long time, we told patients who are getting radiation or chemotherapy to just rest if they felt tired, but at the end of treatment patients, with endometrial cancers and other gynecologic cancers are really three times more likely to experience lower body limitations compared with other cancer survivors like survivors of colorectal or prostate or bladder cancers. In fact, more than half are sedentary, and another 25% are insufficiently active. I think about this time, particularly for patients diagnosed with early-stage disease, as a critical window, almost like pregnancy, where you have an opportunity to change behavior that may have positive spillover effects on cardiac disease, diabetes, or weight loss.
I really try to convince my patients to engage in regular physical activity during treatment, even if it's just walking, because we've found that in postmenopausal women with cancer, those who are less active are at higher risk for death due to cancer and also other causes. I try to encourage patients to track their steps and I ask them about it when I see them because it's a teachable moment, and I want to hold people to be accountable.
Matulonis: I have a patient who's on one of your exercise studies right now who, just yesterday, told me how much it's helping her. That's wonderful. I'd like to shift to talking about another important side effect of treatment that can have an impact certainly during treatment but also a long-lasting one as well. We've seen it in a number of different endometrial cancer drug trials, and that's peripheral neuropathy. We know that carboplatin-paclitaxel leave some patients with long-lasting peripheral neuropathy that really significantly impacts their quality of life negatively. Do you have any suggestions about peripheral neuropathy?
Wright: Oy! Peripheral neuropathy is one of the most vexing issues we face with our patients, and here again, prevention is key. There are a few studies that suggest cryotherapy may help by limiting blood flow to the extremities. I don't think there are great data for that yet, but there's certainly no harm in having patients use the cold socks and gloves, sort of like how we think about cold caps. There also may be a benefit from exercise. Theoretically, exercise enhances blood oxygen saturation and improves parasympathetic nerve activity and increases nerve conduction velocity, which may improve peripheral nerve regeneration and decrease pain. But we're really in the early days of understanding the mechanisms of preventing neuropathy.
We have some ongoing studies testing whether exercise can reduce neuropathy in patients receiving carboplatin-paclitaxel. We're not just talking about walking and using Fitbits. We're talking about really pretty intensive, exercise interventions where people are being pushed to do balance activities and riding bikes and actually dosing the exercise to their exercise capacity. The other thing we need to think about is dose reductions in patients, particularly those who develop grade 3 neuropathies — neuropathies that are interfering with their activities of daily living. Generally, it's recommended that we dose-reduce the offending drug like paclitaxel by about 20% for the remaining cycles. Sometimes, we even have to hold it until the neuropathy recovers to more of a grade 2. Unfortunately, I remember early in my career seeing a woman who had no neuropathy during treatment and then at the end, actually developed profound disabling neuropathy that interfered with her walking.
We know neuropathy can sometimes get worse even after treatment is over. If people have motor symptoms, I have a very low threshold to refer them to physical therapy to make sure that it doesn't interfere with their walking or gait. If they have sensory symptoms, I try to manage it with pregabalin or gabapentin, the key is making sure that you slowly increase the dose of the drugs until people get relief while also making sure that they don't have side effects. That's the thing I've struggled with. Often, people get fatigued. I'm hopeful that we'll get better drugs in the future and that we may have better evidence for other strategies, like acupuncture or yoga.
Matulonis: Yes. In addition to what you're saying here, I think it's important that patients really are communicative with us about their neuropathy because you're right: Certainly, dose reductions, dose holds, and then addition of other medications can be really helpful for them. I'd like to next move on to another really big topic, and that's sexual dysfunction, which is a significant issue for some patients because of their treatment for endometrial cancer, in other words, surgery, radiation therapy, and in some cases really being, affected also by systemic treatment. Can you talk to us about sexual dysfunction, what you recommend to your patients, and what kind of research is being done on this?
Wright: Absolutely. So many women go through menopause after treatment and develop vaginal dryness or discomfort with sexual activity. The problem is when you experience pain or discomfort during sexual activity, your pelvic floor is tense, and that makes it even more painful, particularly for intercourse. This is really analogous: If you think about when you're getting a pap smear or a pelvic exam and you clench, it's painful. There are a few ways to address this. The first is pelvic-floor rehab. It's a form of tailored physical therapy that can help people learn to relax the pelvic floor and regain control of these muscles. Vaginal dilators are also an incredibly important part of pelvic floor rehab because they slowly help the tissues become more elastic and also increase vaginal capacity. There's also treatments for vaginal dryness.
Matulonis: Again, a very common complaint. As oncologists, I think we're always a little reluctant to prescribe topical estrogens. Is there anything we can do about vaginal dryness?
Wright: After treatment, the vaginal walls can become less lubricated and flexible, which leaves the tissues prone to painful tears, cracks, and fissures. Some people experience pain with bleeding or bleeding with sexual activity or burning and urgency with urination and sometimes, more frequent urinary tract infections. There's several ways to treat this, including, rarely, hormone therapy. We're often reluctant to prescribe this as you mentioned, but if people don't have estrogen-driven cancers, we can consider things like rings, estradiol vaginal inserts [Vagifem], or other things, but probably a more standard treatment is the use of moisturizers that rehydrate the tissue. They reduce itching and irritation also. The key is just like a facial moisturizer, they need to be applied frequently, at least three to five times per week before bed. It really needs to be applied both inside the vaginal canal and also to the external tissues. For sexual activity, lubricants can be very helpful to relieve dryness, reduce friction, and protect against pain. They come in water-based forms and silicone-based forms, which sometimes last a bit longer.
Matulonis: Continuing on this topic of sexual dysfunction, Alexi, I do not think as oncologists, we are particularly skilled at talking about and bringing up the subject of sexual dysfunction. What are your recommendations to oncologists as well as to patients to really talking about this subject within the context of a visit?
Wright: I think you're right that, talking about sex and certainly sexual dysfunction is often taboo for patients and sometimes even oncologists. The more we can do to normalize that from the start of treatment, the better. I routinely ask people about their sex lives and intimacy with their partners if they have them because I want to emphasize this is really integral to your quality of life and to your relationships and to who you are. There are effective treatments if you're struggling or you and your partner are having problems. Sometimes, it's actually talking, not just medications or lubricants. I try to plant the seed early, and if they don't pick up on it, I ask about it each time so that they know it's a question that matters to me, and they know it's a safe space to talk about, and also that there are effective things that we can do to help them. So right from the start, we talk about this.
Matulonis: Thanks, Alexi, for those thoughts. We've really covered a lot of ground today so far. But one other topic I'd like to cover — and I'm curious about your thoughts on it — is the increasing use of immune checkpoint inhibitors in the treatment of endometrial cancer, especially in mismatch repair–deficient cancer, advanced cancer. As we're using these drugs more and more, particularly for patients with advanced endometrial cancers, what do you think of the side effects that will affect patients quality of life the most?
Wright: As you know, the most common side effects we see are hypothyroidism, colitis, pneumonitis, but we've also seen a lot of fatigue, rashes, neuropathies, kidney disease, and adrenal insufficiency. Unfortunately, the hypothyroidism and adrenal insufficiency are not reversible and require a lifelong medication, which is something that patients often don't realize and may just stop taking their levothyroxine. For serious side effects like pneumonitis or colitis, we often have to hold treatment and treat patients with prolonged courses of steroids. Sometimes, we have to stop the treatments altogether, which can cause a lot of anxiety. Fortunately, though, in most of the major trials that have been conducted to date, we've seen stable to improved quality of life with the use of checkpoint inhibitors because patients are doing better and responding for longer. We've gotten better at figuring out who to give immunotherapy to particularly, and we're seeing improvements rather than reductions in quality of life.
Matulonis: I'd like to move on to pain. The US is currently in the midst of an unfortunate prolonged opioid crisis. We now we have many different regulations designed to reduce opioid prescribing. Certainly over my career, the prescribing habits have just changed absolutely drastically. You've studied how this has affected cancer patients. Can you tell us more about that?
Wright: As you mentioned, there was a huge push to market opioids in the late 1990s and early 2000s, and pain was the fifth vital sign. It happened at the same time as the liberalization of opioid prescribing. That's one of the factors that helped to drive the opioid crisis. We now know that the peak of prescribing was between 2010 and 2012, but it's come down since then, and it's now largely driven by the use of heroin and synthetic opioids like fentanyl and others. In response to this in 2016, the CDC published guidelines designed to reduce opioid use and a number of states and insurers have passed other laws and prior authorizations to the point that now, we're actually having trouble getting opioids to patients who often need them. It can be pretty burdensome, particularly to get long-acting pain medications. I would say the combination of all of these factors has led to a chilling effect in prescribing. Recently, we wanted to look at an extreme case of this: patients who undoubtedly need access to pain medication. We used data from Medicare to look at a large sample of 320,000 older patients dying from cancer. We looked at trends in prescribing over this time period and really found that there's been a huge drop in prescriptions, both reductions in the number of people who receive opioids when they're dying at the end of life and also the doses that they received if they got the pain medication at all. One of the key things about this study is that we were studying patients dying from cancer where there's no question that pain medication is warranted. During the same period, we found rising rates of pain related emergency department visits at the end of life, suggesting that patients may have more poorly managed pain.
Matulonis: And you found disparities, correct?
Wright: Absolutely. Unfortunately, Black and Hispanic patients dying of cancer were significantly less likely to receive short- and long-acting opioids. When they did, they also received lower daily doses compared with White patients. Shockingly, they were also more likely to undergo urine drug screening tests compared with White patients. Obviously, there's no convincing evidence that patients of color experience pain differently or prefer their pain to be under medicated. These findings suggest that there's conscious or unconscious racial biases that may lead clinicians to prescribe fewer or less potent pain meds to patients of color and that they also may employ more risk-reduction strategies.
Matulonis: Alexi, you recently received a large grant to study and change this, correct?
Wright: Yes. We're now expanding our work to really focus on access to pain medication across the cancer trajectory, including at the time of diagnosis. Are people getting fewer medications at the time of surgery? Maybe that's correct in some instances because we know that at the time of diagnosis, we're definitely finding there are other ways to treat pain, the enhanced recovery after surgery (ERAS) interventions, trying to mobilize people early and use acetaminophen and chew gum, ibuprofen, and other things. But also, during the treatment period, we want to look at disparities in access to pain medication when people have chronic cancers as well as at the end of life. We're really trying to drill down where these disparities are happening. Is it happening at the neighborhood level or patient level? They can't get access to meds in pharmacies because of stock outs? Is it happening between patients and providers or are people of color going to different healthcare systems? Ultimately, we're going to design an intervention to change this.
Matulonis: Thank you so much for all your work on studying opioids and really realizing that quite significant disparities occur with prescribing. Can you talk a little bit about how best to treat pain in our patients with nonopioid types of therapies, and this pain can be certainly from neuropathy-related to chemotherapy-related, and obviously, for certain patients, it would be end-of-life pain related to tumor burden.
Wright: There's growing evidence, actually, that there are other strategies beyond opioids and beyond things like over the counter remedies like ibuprofen or Tylenol to treat pain and they really actually get at mindfulness. There are, again, psychological interventions that can sometimes be helpful because they not only address the pain but also are what we call transdiagnostic, meaning that they can address the pain but also the anxiety invoked by pain or the mood symptoms to help people disengage, similarly to how I was talking about disengaging from the rumination around fatigue.
Obviously, I don't want to suggest that people's pain is in their head, but often, treating sort of the side effects of pain and the worry that accompanies it can be quite helpful to interrupt that cycle.
Matulonis: I've definitely noticed that when there's psychological strife happening for the patient within the patient's family, that pain can increase, and I can even see that if we're talking about a difficult subject during our visit. So, thank you again for all that.
I'm going to wind down in terms of the types of quality-of-life problems that our patients experience and finish up with mental health, which is not a small topic at all. What are your recommendations for helping our patients with their mental health during endometrial cancer treatment, diagnosis, etc.?
Wright: Mental health is sometimes tricky. I always recommend and try to normalize the use of social workers or psychologists in therapy because many people have biases against it. I just try to explain to them that nearly half my practice sees a social worker or a third of people, and that's very normal. Therapy is a place where you can share things that you might not feel comfortable sharing with your family members who have a vested interest in things. But exercise has actually been shown to improve mental health as well. In addition to helping prevent neuropathy to helping prevent fatigue, I think doing some regular exercise and getting outside is really important. Obviously, if people have clinical depression or anxiety, then medication is really important. I will frequently refer people to psychiatry or start them on antidepressants if needed to sort of give them a floor to help people cope with these difficult times.
Matulonis: Alexi, thank you so much for your expertise, insight and research on quality of life.
Wright: Thanks for having me. I'm so glad you're featuring this. It's really important for our patients, and it's lovely to talk to you.
Matulonis: Today we've talked to Dr Alexi Wright about how she manages troublesome quality-of-life issues that negatively impact our patients, such as peripheral neuropathy, fatigue, and sexual dysfunction. We discussed her recommendations about how to help patients with their mental health and she discussed her multitude and many research projects and interests. Thank you so much for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on endometrial cancer. This is Dr Ursula Matulonis for the Medscape InDiscussion Endometrial Cancer podcast.
Resources
Cancer Survivorship Guidelines
Research Status of Internet-Delivered Cognitive Behavioral Therapy in Cancer Patients
CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016
US Trends in Opioid Access Among Patients With Poor Prognosis Cancer Near the End-of-Life
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Cite this: How Can Oncologists Address Endometrial Cancer Survivorship Needs to Improve Patient Quality of Life? - Medscape - Jun 25, 2024.
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