Kristen N. Ganjoo, MD
Many uterine leiomyosarcomas present as metastatic disease after having been misdiagnosed as a fibroid, explained Kristen N. Ganjoo, MD, and although there are treatment options for these patients, an early and accurate diagnosis is the only chance of cure.
“Unfortunately, it’s really hard to diagnose patients based on an ultrasound or magnetic resonance imaging. If you do a biopsy, you may biopsy a part that is nondiagnostic,” said Ganjoo, an associate professor of medicine at Stanford University Medical Center. “Usually, the main key is rapid growth in the abdomen. If a patient has an ultrasound, and then 6 months later, it has doubled in size, then it’s a uterine sarcoma.”
If a uterine leiomyosarcoma spreads into the abdomen, Ganjoo noted physicians have several chemotherapies to choose from, including the combination of gemcitabine/docetaxel and doxorubicin/olaratumab (Lartruvo).
Immunotherapy is under investigation, but it has shown modest activity when used as a single agent in this setting. A phase II study (NCT02500797) examining the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated efficacy in patients with metastatic sarcoma, responses of which extended to those with uterine leiomyosarcoma, said Ganjoo.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Ganjoo discussed the diagnosis, presentation, and management of patients with uterine leiomyosarcoma.
OncLive: How common are uterine leiomyosarcomas?
Uterine sarcomas are very rare. There are 3 main types of sarcomas found in the uterus: leiomyosarcoma—which is the most common—undifferentiated sarcoma, and endometrial stromal sarcoma. There are about 5000 cases of uterine sarcomas in the United States every year. The only treatment that can possibly cure them is surgery. Early diagnosis is extremely important. If the disease is metastatic, then it becomes incurable.
Do the majority of patients present as metastatic by the time they are given a diagnosis?
Usually, these tumors are found in younger women. Many of these women are diagnosed with fibroids, which are a benign form of smooth muscle, [also known as] leiomyomas. When they are discovered, usually there is tumor growth. The abdominal mass shows, and then there’s bleeding; at that point, it’s metastatic. Some patients who are presumed to have fibroids will undergo a procedure called morcellation, where the uterus is broken into parts and then they are suctioned out. At the end of the day, the [surgeon] discovers that it’s really a leiomyosarcoma after everything has spread in the abdomen. Of 350 patients who have a fibroid, 1 will have a leiomyosarcoma. Of those patients who have a morcellation, almost all patients [have disease that] spreads and recurs.
What treatment options are available in this space?
The treatment is surgery. If the patient has early-stage disease, we really don’t have good studies to prove that adjuvant chemotherapy helps prevent recurrence. Some phase II studies have shown some promise. The phase III study didn’t have enough accrual, so that study was abandoned. Generally, we don’t recommend chemotherapy after surgery for stage I or II disease. If it’s a larger tumor or more of an aggressive stage II disease, then we usually recommend chemotherapy to prevent metastatic lesions from growing. For patients with early-stage disease, [the options are] really just surgery and possibly radiation therapy to ensure that there is no local recurrence.
For patients who have metastatic disease, several different kinds of treatments are available. Several chemotherapies were approved over the past 5 years. For 20 to 30 years, we just had 1 chemotherapy, but now we have multiple—especially for leiomyosarcomas. We’re testing immunotherapy now. We haven’t had much luck with immunotherapy in uterine leiomyosarcomas, but that’s still a potential option.
Additionally, we have targeted therapies, such as pazopanib [Votrient], which is a VEGF inhibitor that has been approved by the FDA for sarcomas. Most patients with leiomyosarcoma will receive all these treatments at some point. One big challenge is deciding what to start patients on first. These patients live a long time. Throughout their lives, they’ll receive [doxorubicin] first and gemcitabine/docetaxel second, or vice versa. Then there are other treatments on the list.
Could you elaborate on patient selection for these types of therapies?
The combination of doxorubicin and olaratumab is the standard of care for first-line therapy. Many physicians think that uterine leiomyosarcomas should be treated with gemcitabine/docetaxel because the studies that were done for uterine leiomyosarcoma used that combination. Doxorubicin has been compared with gemcitabine and docetaxel and has fewer adverse events, so that’s my first go-to chemotherapy.
The problem is, some patients have congestive heart failure and therefore [may not be able to] receive certain drugs; it depends on their comorbidities. We have to look at possible adverse events and gauge what to choose for each patient. First-line therapy is either doxorubicin/olaratumab or gemcitabine/docetaxel. For third- or fourth-line therapies, you can go with trabectedin [Yondelis], pazopanib, or dacarbazine. There are several options that most patients go through at some point in their lifespan.
Is immunotherapy being explored as a single agent or in combination?
The study that was done by Suzanne George, MD, at Dana-Farber Cancer Institute used nivolumab as a single agent, and that didn’t show much response in uterine leiomyosarcomas. However, [results from] the Alliance [for Clinical Trials in Oncology] trials showed that the combination of nivolumab and ipilimumab had a 4-month median survival advantage for patients with sarcoma, which is great.
Any increase in survival is wonderful. Some of the patients with leiomyosarcoma also responded nicely to the combination therapy. Now I’m using the combination in metastatic uterine leiomyosarcomas as well. We’ve had some good responses that have not been published yet. Also, at some point during chemoimmunotherapy, patients can get radiation, cryoablation, or microwave ablation. That approach seems to potentiate the effects of the immunotherapy.
Are any new agents in development in this space?
The National Cancer Institute tested cabozantinib [Cabometyx], which is already approved for renal cell cancer. I’ve treated several patients on clinical trial with that drug who have uterine leiomyosarcomas, and they had a great response. It’s a VEGF inhibitor like pazopanib, but it affects multiple other targets as well. That study has completed, so we’re hoping we can get results on all those patients. Eribulin [Halaven] was compared with dacarbazine, but the FDA only approved it for patients with liposarcomas; it’s an option for patients with leiomyosarcoma who have had dacarbazine in the past.
Is there anything else you would like to emphasize?
We have treated a lot of patients with leiomyosarcoma who have liver-only disease. They have a uterine sarcoma that was resected, and then they present with multiple liver lesions. We’ve had very good luck with radioembolization, [specifically] yttrium-90 liquid radiation. That’s also an option I want patients to explore. In terms of focal therapy, we have cryoablation, microwave ablation, or radioembolization.