Endometrial Carcinoma: Clinical Scenario 1

Krishnansu Tewari, MD: 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.

David O’Malley, MD: 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 JCO [Journal of Clinical Oncology] 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?

Krishnansu Tewari, MD: 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?

Bradley Monk, MD, FACOG, FACS: 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.

Krishnansu Tewari, MD: Do they need to have measurable disease for that study?

Bradley Monk, MD, FACOG, FACS: 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 New England Journal of Medicine, standard chemotherapy vs adding radiation, and it was negative. It was published in the New England Journal 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.

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

Bradley Monk, MD, FACOG, FACS: 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.

David O’Malley, MD: 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?

Bradley Monk, MD, FACOG, FACS: What was the control arm of the PORTEC-3 trial? Radiation.

David O’Malley, MD: That was the radiation.

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

David O’Malley, MD: 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.

Krishnansu Tewari, MD: I agree with that too.

Bradley Monk, MD, FACOG, FACS: 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?

Krishnansu Tewari, MD: 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.

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

David O’Malley, MD: 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 TP53?

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

Transcript edited for clarity.