When facing a frightening new cancer diagnosis, some people ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Jane Meisel, MD, how she would handle her own advanced endometrial cancer. Dr. Meisel is Associate Professor of Hematology and Medical Oncology at Winship Cancer Institute at Emory University in Atlanta, GA.
Curious Dr. George: Please consider a hypothetical scenario in which, as a very busy gynecologic and breast oncologist, you noticed that your menstrual periods had recently become heavier and more prolonged, but you thought little about it. But now you have lost 8 pounds without a change of diet or exercise. You consult your gynecologist who finds a normal pelvic exam but is concerned by possible ascites (fluid buildup in the abdomen). She performs an endometrial biopsy, and after abdominal ultrasound, aspirates 10 ml of clear peritoneal fluid. The endometrial biopsy yields a diagnosis of poorly differentiated adenocarcinoma, and the peritoneal fluid is found to contain malignant cells. How do you proceed?
Jane Meisel, MD: The treatment options for endometrial cancer have evolved significantly since I finished my oncology fellowship in 2015, so while advanced endometrial cancer is never a diagnosis one wants to receive, patients have many more potential treatment options now than they did even five years ago. I stress this to patients in clinic every day, and I would try to remind myself of this fact as well, even though I know it might be hard to think rationally like this in the wake of a difficult diagnosis.
Endometrial cancer, when it metastasizes, is most likely to metastasize locally in the pelvis, to pelvic and para-aortic nodes, the peritoneum, and the lungs. In any situation where metastatic cancer is suspected, a biopsy is key, and there is much my treating physicians and I would be able to learn about the cancer from the biopsy. First, the histology—is it endometrioid, clear cell, or serous? Serous and clear cell are associated with worse overall survival compared to endometrioid cancers, and clear cell cancers tend to be more chemoresistant than other subtypes. If it were endometrioid, we would want to do receptor testing for estrogen and progesterone, as this can help with treatment planning; and if it were serous, we would want to do HER2 testing for the same reasons.
All patients with endometrial cancer should have mismatch repair protein (MMR) or microsatellite instability (MSI) testing to understand options for immunotherapy. Somatic mutation testing is often also done (using a next-generation sequencing panel), but this could be done at a point of progression rather than at initial diagnosis, since the first-line treatment is unlikely to change regardless of NGS results.
Given that I am young and healthy, if I had never been treated for endometrial cancer before (in the early-stage setting) and was felt to be a good surgical candidate based on extent of disease, then surgical cytoreduction would be appropriate, followed by adjuvant chemotherapy. If I were not a surgical candidate or if this were a metastatic recurrence (as opposed to de novo disease), chemotherapy as an initial treatment would be appropriate.
The first-line chemotherapy used for advanced endometrial cancer is almost uniformly carboplatin plus paclitaxel. In a clinical trial known as GOG 209, this combination was compared with a cisplatin triplet-based regimen (cisplatin, doxorubicin and paclitaxel) and it was found to have a similar overall response rate, similar progression-free survival, and similar overall survival, with much lower rates of neuropathy and less overall toxicity.
I always tell my patients with advanced or metastatic cancer that the goals of treatment are to help you live as long as you can and as well as you can—and the “living well” part is very important. So, carboplatin and paclitaxel would likely be my first line of treatment (with trastuzumab if I had serous cancer and were HER2+, given that trastuzumab improves progression-free and overall survival in this situation).
While on carboplatin and paclitaxel (plus or minus trastuzumab), I would monitor with CT chest/abdomen/pelvis every three cycles (or more often if I developed signs of progression while on treatment). There is not a distinct tumor marker defined for endometrial cancer, but in some cases (particularly with high-grade serous endometrial cancer), CA 125 can be elevated at diagnosis, and if that’s the case, can be helpful to follow with each cycle or two to help get a window into the response to treatment.
Upon progression or intolerance of chemotherapy +/- trastuzumab, additional options would have to be considered, and along with that, some of the histologic variables previously discussed. If my tumor were mismatch-repair deficient, had evidence of microsatellite instability, or had a high tumor mutation burden (as assessed via genomic testing), immune checkpoint inhibitors such as pembrolizumab or dostarlimab could be used as single agents. These are very well-tolerated agents when given on their own. Endocrine therapy is also an option, particularly for patients who have hormone-receptor positive, low-grade endometrioid cancer. Otherwise, progression would depend on the treatment-free interval.
If my cancer had not progressed until six months or more after completing my last dose of platinum-based chemotherapy (platinum-sensitive), I could be re-treated with carboplatin and paclitaxel again. If my cancer had come back sooner (platinum-resistant is typically defined as recurrence within six months of last platinum agent), then I would consider pembrolizumab plus the oral VEGF receptor inhibitor lenvatinib, which is effective in patients with advanced endometrial cancer that is not MSI-high or mismatch-repair deficient. This could also be employed after another round of platinum-based chemotherapy, if I were platinum-sensitive initially but after another round of platinum-based chemotherapy, either became intolerant of side effects or treatment resistant.
There are other alternatives as well, such as liposomal doxorubin, bevacizumab, and re-treatment with taxanes. There are also a number of clinical trials that are very exciting; among them, trials looking at additional anti-HER2 targeted agents in patients with HER2+ high-grade serous cancer (such as trastuzumab deruxtecan and tucatinib), and trials evaluating different endocrine therapy options for patients with hormone-sensitive endometrial cancer (CDK 4/6 inhibitors and serum estrogen receptor downregulators are good examples).
Overall, I would try to pace myself, as advanced cancer is a marathon rather than a sprint, and make sure that above all, I felt comfortable with my treatment team and in our shared decision making every step of the way.
Dr. Meisel can be reached at firstname.lastname@example.org.