 Actually, I think Brad has the next case.

 I have the pleasure of working here in Arizona where there’s a very large Native American population. It’s my pleasure to take care of them and collaborate closely with the Indian Health Service. Obesity is a serious problem there. We’ve learned and we’ve already addressed that how these patients are treated depends on the type of provider. This idea that they need chemotherapy as an adjuvant treatment is important, but sometimes the patient will see someone who may not be as familiar and say, “We’ve given radiation forever.” This particular patient has 3 positive nodes and needs systemic therapy. If you want to give vaginal brachytherapy, that’s fine. We already talked about the negative GOG-258 trial in the 

, presented by Daniela Matei, MD, which showed that adding radiation to systemic therapy did not improve survival.

This woman got radiation, and I didn’t treat her. Since it was done outside of a high-volume center, this center did not have the molecular testing. We had realized that and were trying to work through the state. I want to ask Krish, you, or Dave, when you do mismatch repair deficiency testing, when do you do germline to look for Lynch syndrome [hereditary nonpolyposis colorectal cancer]?

 If they have loss of any of these proteins, as long as it’s not MLH1,or it is MLH1 and promoter hypomethylation has been ruled out, we send them for genetic counseling and we get them tested for Lynch syndrome.

 Do you send them to a counselor, or do you counsel them at the point of contact in your clinic?

 It depends on where I am. At UCI [University of California, Irvine], we counsel them, and we order the tests ourselves. At one of our other sites, we have an organized genetics program that sees the patient the same day in our office, and they get counseled right there.

 You begin to develop 2 groups of patients who are MSI [microsatellite instability]-high or mismatch repair deficient. One group is a promotor hypomethylation, MLH1 generally, so that’s epigenetic silencing or epigenetic loss. The other group can have a mutated gene that can either be somatic or germline. I think we’re learning, Dave, that those sorts of subsets are different. Tell us about how that group of patients would respond differently.

 We’ve learned a lot from the colorectal data, and I think as we look at the mutated gene group, clearly those are benefiting the most. We need to better describe those patients and further refine our testing, but again, we continue to do that. We have some research that is just coming out and is now accepted for publication. This research calls into question the thought that we should only send certain patients who have loss of one of the mismatch repair proteins to get genetic testing. We are identifying another potential 10% to 15% of patients with genetic predispositions beyond even Lynch syndrome, particularly in our high-risk type of uterine cancer. At the current time, I’m still going to treat patients with hypomethylated versus genetic abnormalities with a single-agent PD-1 inhibitor, but I think we need to answer that question more clearly. What do you guys think?

 Germline testing is becoming so cheap and so prevalent; it’s just easy. To talk yourself out of it when a woman has cancer, particularly at a young age–I hear you. To your point, Krish, you can counsel those patients right at the point of care, and patients want to know what their germline testing shows. I think that’s evolving.

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Experts explain the need for germline testing and genetic counseling for patients with endometrial carcinoma as demonstrated by a patient case.

Endometrial Carcinoma: Clinical Case Scenario 2

 This patient got started on 20 mg of lenvatinib along with pembrolizumab. As you know from the trial, most patients end up getting dose reduced. How do you dose the drug, Brad?

 I follow the recipe. Just because you reduce the dose, doesn’t mean you started at the wrong dose. Patients get dose reduced on our PARP inhibitors in ovarian cancer, paclitaxel, all this. If the patient is protocol-like—healthy and has good end-organ function—then I’d treat her like the protocol. There are exceptions, and Dave’s going to tell us about what those exceptions are, where patients wouldn’t have been eligible because they’re too fragile. That would be a lower dose. It goes 20, 14, 10, 8 mg. Dave, when do you not use 20 mg as a starting dose?

It’s exactly what you’re saying with regard to performance status. I have a patient who’s quite frail. We call her an ECOG 2; she’s really a 3. You look at that and the creatinine clearance, which we’ve reduced if we look at the investigator brochure. You start at 10 mL/min, and that’s at 40 mL/min now. I always check to make sure what my calculated creatinine clearance is. I know it’s 10 mL/min, but the creatinine clearance said 40 mL/min. If I have a question in a patient who’s older, I’ll get a 24-hour measured urine. Brad and I go back and forth on this all the time, Krish. I’m pragmatic to a fault. When I have to reduce—and I know that two-thirds of patients are going to need to be reduced, maybe even 80% but probably two-thirds to three-quarters—I start at 18 mL/min. I know it’s not the formula and it’s not the FDA indication, but then they got the 10, the two 4 mL/min. When I have to go down to 14 mL/min, I don’t have to wait for a new script. I don’t have to call anything in. I just go take the 10 mL/min and the 4 mL/min. From that pragmatic standpoint, that’s what we started. It’s not an extra prescription and it allows you to dose reduce without missing a day if that’s appropriate.

 It’s all about efficiency. In the historical past, they’d have to pay another co-pay, but now there’s a drug replacement program. If the system isn’t very fast, then there can be a big interruption. I want to emphasize that point that you made: 18 mL/min is pretty close to 20 mL/min. But it’s not financial anymore; it’s about the efficiency of your claim.

 I want to emphasize Brad’s point. If they’re very protocol-like, I encourage starting at 20 mL/min. There’s some thought that the loading dose in the beginning is important, even if you ultimately have to dose reduce.

A lot of these patients are coming in symptomatic. When we look at the KEYNOTE-775 trial and Vicky Makker, who presented lenvatinib-pembrolizumab vs chemotherapy in patients previously treated in the 

 in January 2022, those response rates were doubled in the lenvatinib-pembrolizumab arm, 30 vs 15. You have survival advantage and PFS [progression-free survival] advantage. Even though we had to dose reduce two-thirds to three-quarters of patients, the quality of life was the same. Once you figure out that dosing— it usually takes a couple of months—their tolerance seems to be quite good, particularly when you can get disease reduction and then maintenance.

 Krish, have you seen a lot of hypertension with the lenvatinib anti-VEGF activity?

 No, not a lot. I’ve seen a little but mainly fatigue. That’s the biggest issue my patients have.

 As the audience knows, Krish developed bevacizumab in cervix and ovarian cancer, so you have a lot of experience with bevacizumab and other anti-VEGF therapies. They probably check their blood pressure at home. That’s what we learn together, and you have nursing staff and support, which are key. It’s a team approach, no question.

The team approach is huge. Even though you don’t see as much as we originally thought about it, I make sure those patients have access to a prescription for antihypertensives. They don’t have to get it, but they have to have access. In addition, what we started instituting with the use of video visits is that APPs [advanced practice providers] have video visits weekly to make sure we’re keeping on top of this. I’d strongly encourage that. Now that we can do weekly video visits, let’s get them on the phone, on the video weekly, and talk about the symptoms they’re having to keep on top of it.

 In the state of Arizona, it’s the law that they have to reimburse for that, so we’re able to keep our doors open. The other thing we’ve learned is they have to stop the lenvatinib if the blood pressure is too high, so it’s not the medication or the antihypertensive. We tell outpatients to stop if they get somewhere between 160 and 170; 160 begins to make me nervous.

They’ll go fairly quickly, and then suddenly they’re in trouble. You’re right. With the short half-life, it will get better all the time. But I like them to have that prescription in their hand.

 That’s a great idea. Brilliant as usual.

Drs Bradley Monk and David O’Malley explain dose reduction in endometrial carcinoma treatment based on clinical trial data.

Dose Reduction in Endometrial Carcinoma Treatment

 Hello, my name is Krish Tewari. I’m a professor and division director of gynecologic oncology at UC Irvine [the University of California, Irvine]. I’m joined by Dr Bradley Monk from the University of Creighton and the University of Arizona College of Medicine in Phoenix. I’m also joined by my good friend Dr David O’Malley from The Ohio State University Comprehensive Cancer Center. We’re going to be talking about endometrial cancer.

I’m going to start with an interesting patient. I have a 55-year-old with a medical history that’s notable for high blood pressure, hypercholesterolemia, and type 2 diabetes. She was diagnosed after surgery with a FIGO [International Federation of Obstetrics and Gynecology] stage IIIC1 endometrioid adenocarcinoma of the uterus. She had undergone robotic hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymphatic mapping. Interestingly, her pathology indicated that the tumor was MSI [microsatellite instability] stable, and postoperative imaging was negative for metastatic disease. Of course, this was done once we found out that she had a nodal metastasis. The patient was counseled accordingly and started adjuvant systemic therapy with a platinum and paclitaxel, carboplatin specifically. David, what are your initial impressions? This is the type of patient many of us see every month.

 My first question, Krish, is why didn’t you get her on protocol, the GOG-3053 trial or the KEYNOTE-B21 trial? It’s a perfect opportunity. She’s MSI stable and MMR [mismatch repair] proficient, but as we look at these patients, clearly the carboplatin-paclitaxel backbone is important. Can we do better with loco-regional disease? The biggest question for me is, do you add radiation? Do you add the whole pelvic radiation? As I’m going through this, I’m thinking about the PORTEC-3 trial, both the molecular and clinical outcomes. The recent report in 

] shows there’s some survival advantage when we bring chemotherapy onto radiation backbone. The biggest question always on my mind for these patients is, how much more am I adding with regard to the radiation compared with the balance of the long-term toxicities? It’s a 55-year-old woman; she has 30 years to live in the long-term implications of radiations. What do you guys think?

 Brad, do you want to take that and frame it in the context of the subgroup analysis of stage III patients in the GOG-0258 trial?

 I love seeing you guys. I love hearing you guys. That study you’re referring to, Dave, is called KEYNOTE-B21. It takes the global standard of carboplatin-paclitaxel and randomizes them to pembrolizumab or placebo. I love that study. That’s what would have happened at my center.

 Do they need to have measurable disease for that study?

 They don’t. It’s an adjuvant study, so we have 2 buckets. We have the adjuvant patient, which could be uterine serous cancer with no metastatic disease or this patient with stage IIIC1. The other bucket is stage IV recurrent. All the phase 3 trials we’re doing are stage IV recurrent except for that 1 adjuvant study, which is a massive study. GOG-0258 was a randomized phase 3 trial published in the 

, standard chemotherapy vs adding radiation, and it was negative. It was published in the 

 to teach people to stop doing the wrong thing—adding radiation to chemotherapy—because it was a negative study. The subset analysis suggests there might be subsets. I don’t care; it’s negative. You shouldn’t do radiation in this setting.

 GOG-99 was a negative study, but for patients with early stage, high-risk endometrial cancer, we follow the subset analysis in GOG-99.

 Our audience doesn’t know these numbers. GOG-99 was adjuvant therapy: you had a hysterectomy, you got radiation or not, and there was maybe a benefit in patients who had deeper invasion in higher-risk tumors. That created the current study, which is now the standard, pelvic radiation vs chemotherapy radiation, which is called GOG-0249. There’s no benefit of dual-modality therapy. The reason radiation is the standard in those patients is because the lymph nodes are negative. You have a patient, you do the nodes, and you assess the risk. Even if the nodes are negative, such as a serous cancer or an adjuvant chemotherapy, and if the risk is high because the nodes are positive, then you give her chemotherapy. The role of radiation is undefined.

 I can’t argue. When we look at survival advantage, until the PORTEC-3 trial, we didn’t have a survival advantage by adding radiation. You could argue the survival advantage wasn’t the radiation. It was chemotherapy added to the radiation. You still don’t have survival advantage, right?

 What was the control arm of the PORTEC-3 trial? Radiation.

 Yes, as the roll-on control arm. It’s another irrelevant study, and I don’t know why we talk about it.

We have to look at the loco­-regional recurrence in GOG-0258. We know the percentage of these patients who get salvage if they have a regional lymph node metastasis; it’s very low. If I have that subset with the metastatic lymph node, it’s very reasonable to have the conversation with her about radiation. Debating you to say you clearly should add radiation to chemotherapy, I’m not going to win, but if you’re going to treat with 1 modality, treat with chemotherapy.

 Krish, if you’re going to add radiation to chemotherapy, how do you do that? Do you give the radiation first, do you sandwich it, or do you give it at the end of the chemotherapy because the chemotherapy is the dominant modality?

I don’t give radiation for advanced-stage cases. We all have plenty of examples of patients who had nodal metastases only, and they’ve been salvaged with chemotherapy. For intraperitoneal metastases plus nodal metastases, with or without nodal metastases, it’s very difficult to save those people.

 That’s the other bucket: stage IV recurrent. Dr O’Malley, it’s 2 to 1. You’re outvoted.

I told you I wasn’t going to win this, Krish, but it’s a reasonable alternative. How would the molecular components to these tumors potentially change? Are you checking 

 I was going to move on to biomarkers, so let’s talk about that next.

Oncologists describe a typical presentation of endometrial carcinoma and debate the implications of radiation treatment.

Bradley Monk, MD

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Endometrial Carcinoma: Clinical Case Scenario 2

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Endometrial Carcinoma: Clinical Scenario 1