Uterine Leiomyosarcoma: Rare Tumor in Clinical Trials

George Monemvasitis; Martee L. Hensley, MD, MSc

Disclosures

November 19, 2014

Editor's Note: Uterine leiomyosarcomas are aggressive, heterogeneous cancers associated with high rates of progression and recurrence—and poor outcome. Uterine sarcomas as a group are uncommon cancers, representing approximately 8% of all uterine malignancies[1]; of these uterine sarcomas, 42%-60% are of the leiomyosarcoma subtype.[2] The rarity of the disease, however, has not hampered research efforts to study its etiology and discover newer interventions.

In an interview with Medscape, Martee L. Hensley, MD, MSc, a medical oncologist with the Gynecologic Medical Oncology Service, Department of Medicine, at Memorial Sloan Kettering Cancer Center in New York, discussed the lack of presurgical modalities to differentiate benign uterine fibroids from malignancy, the controversy over morcellation, the deficiencies of current staging systems, and the challenges and initiatives undertaken to manage uterine leiomyosarcoma.

Childhood Radiation Increases Risk for Pelvic Sarcomas

Medscape: Are there identifiable risk factors? What role does genetics play?

Dr Hensley: The vast majority of women who have this cancer have no identifiable genetic risk factor. That being said, some factors increase the risk for pelvic sarcomas. Women who have had exposure to treatment-dose radiation in childhood or infancy are at an increased risk of developing secondary malignancies in their young adult life; one of the most common secondary malignancies is uterine sarcoma. Adult cancer survivors who received radiation in childhood for retinoblastoma or rhabdomyosarcoma, for example, are at increased risk for uterine sarcoma.[3]

In terms of genetic predisposition, the syndrome called Li-Fraumeni, which is an inherited mutation in the tumor suppressor gene p53, predisposes patients to a spectrum of cancers that includes sarcoma, including uterine leiomyosarcoma.[1] Li-Fraumeni is a very rare genetic syndrome; most people with a uterine sarcoma will not have an identifiable risk factor or genetic predisposition.

Medscape: In the examination of a suspected uterine mass, is there a way to distinguish between a leiomyoma and a leiomyosarcoma by nonsurgical means?

Dr Hensley: Unfortunately, we often don't know before surgery whether a mass in the uterus is a benign fibroid or a malignant leiomyosarcoma or other uterine cancer. There is no test or imaging modality that can definitively determine whether a mass thought to be a fibroid is a cancer or not.

There might be some indicators that would increase the level of suspicion, such as when a mass thought to be a fibroid grows rapidly in a woman who is past her menopause. That would be somewhat unusual, because most fibroids would regress during menopause.

Sometimes, MRI done before surgery will suggest a mass has characteristics that could be malignant. The absence of those findings, however, does not necessarily indicate everything found at surgery will be benign. That being said, the chance that a mass actually turns out to be cancer at the time of surgery is still felt to be low, ranging from about 1 case in 300 to 1 case in 1000.[1]

Medscape: Should we biopsy uterine masses to rule out sarcoma? What is the likelihood that these biopsies would even be accurate?

Dr Hensley: Usually, we cannot biopsy to find out what's going on before we proceed with surgery. The tissue is not nearly as accessible as a breast mass, for example. Getting past all those important organs—the colon, bladder, and bowel—to biopsy what might be a fibroid would probably introduce more risk than it's worth.

On the other hand, you might wonder, why not perform an endometrial biopsy, which is an in-office procedure and a more accessible route? Alternatively, why not do a more extensive assessment of the endometrium, such as dilation and curettage (D&C), which is an operating room procedure? But both of these procedures would only access the lining of the uterus, which is the endometrium, whereas most sarcomas arise in the muscle wall of the uterus, which lies deeper than the endometrium. You may not get to the malignant, or the potentially malignant, tissue from an endometrial biopsy or a D&C.

Specialized Surgery, Pathology Could Make All the Difference

Medscape: What symptoms would increase suspicion of malignancy, and at what point in a patient's management should a referral to a specialized center be made?

Dr Hensley: A postmenopausal woman might present with vaginal bleeding. A premenopausal woman might present with abnormal vaginal bleeding, which could be a change in the type, frequency, or heaviness of flow. Sometimes there is no bleeding, and a woman might feel persistent bloating and pain and then have a mass or an abnormally enlarged uterus found during a pelvic examination. That would often prompt imaging with sonography, CT, or MRI.

A mass initially thought to be a fibroid that is growing in size in a woman who is past her menopause would be a flag for her to consider surgery with a gynecologic oncologist; opting not to have a morcellation-type procedure would be another consideration. Certain MRI characteristics that show particular heterogeneity or areas of necrosis in the mass may be suggestive of malignancy.[4] A woman whose uterine mass has those characteristics might want to consider surgery with a gynecologic oncologist.

Another advantage of undergoing surgery in a specialized hospital is access to expert histologic review by gynecologic sarcoma-experienced pathologists. Determining the particular type of uterine sarcoma and classifying it as one of various subtypes require highly specialized skills. The diagnosis of uterine sarcoma is best done in the hands of a gynecologic pathologist who sees a lot of gynecologic sarcomas. There's great nuance in the diagnosis and behavior of these cancers, and having the tissue expertly reviewed either at initial diagnosis or once the mass is found to be malignant is really critical.

Treatment in a specialized center, where the doctors across the team have vast experience in managing sarcomas, is likely to optimize the patient's outcome. That means surgical skills, pathology skills, and medical oncology expertise, as well as access to newer interventions, such as radiofrequency ablation or special surgical procedures. All of these interventions may be involved in the management of a patient with sarcoma during the course of her disease. Having access to people with deep experience in these rare diseases probably does help people do better overall.

Medscape: The relative safety or potential harm of removing uterine masses by morcellation has been a recent subject of debate. Should we be removing masses en bloc, or is division acceptable?

Dr Hensley: In cancer medicine, we generally like tumor masses to be completely removed intact and not broken up and spread around before they are removed. This is what is behind the recent controversy about whether to break up tumors with power morcellators at the time of surgery when you don't know whether the mass is a tumor or a benign fibroid.[5,6,7,8] If a woman is entertaining the idea of having a hysterectomy for fibroids, it is certainly worthwhile for her to discuss with her surgeon whether there is suspicion of malignancy, and if so, what the recommended surgical approach in that situation would be.

Nomogram: An Improved Prognostic Tool

Medscape: What staging systems and other tools can be used to estimate the prognosis of a patient with uterine leiomyosarcoma?

Dr Hensley: Traditional staging systems come from two sources. One is the International Federation of Gynecology and Obstetrics (FIGO), and this staging system uses anatomical involvement to stage the tumors. Tumor confined to the uterus is stage I cancer; tumor that has spread to distant organs is stage IV. For tumors at either end of the spectrum, this staging system can be reasonably prognostic, but for tumors that fall in between, the FIGO system doesn't perform that well as a predictor for overall survival.

The American Joint Committee on Cancer (AJCC) has a staging system for sarcomas that is a little different. It incorporates size—so tumors bigger than 5 cm are worse than tumors that are smaller than 5 cm—and it also incorporates grade. But AJCC staging for uterine sarcomas also does not perform perfectly in terms of predicting outcome for a given patient.[9]

We developed a nomogram at Memorial Sloan Kettering to explore the idea of using nonanatomical and non-grade–related variables to determine overall survival using a database of uterine leiomyosarcomas. In that work,[10,11] we found that certain variables, including patient age, tumor size, tumor grade, tumor extension to the cervix, mitotic rate (the number of cells dividing in any 10 microscope fields), and presence or absence of distant spread, were important in describing the overall survival of a given patient with uterine leiomyosarcoma specifically. That nomogram is useful to help understand how patients are likely to do in terms of 5-year survival.

Medscape: Is it necessary to remove lymph nodes and ovaries when uterine leiomyosarcoma is diagnosed?

Dr Hensley: In ovarian cancer or high-grade endometrial cancers, the chance of occult involvement of the lymph nodes is moderate to moderately high; that is not the case in patients who have a uterine leiomyosarcoma that is limited to the uterus. If the lymph nodes and the ovaries appear normal to the surgeon and there is no evidence of distant spread beyond the uterus, it is not necessary to remove the lymph nodes and the ovaries. However, because some of these tumors express estrogen receptor or progesterone receptor, we sometimes are more comfortable if the patient does not maintain ovarian function.[12]

If the patient was already at the time of her menopause or close to the time of her menopause and she was undergoing surgery for an identified or suspected leiomyosarcoma, we might counsel the patient about the option of having the ovaries removed, but it's not standard to do so. The chance you would actually find cancer in the ovaries is very, very low.[2,13]

Will Adjuvant Chemotherapy Improve Survival?

Medscape: What role does chemotherapy or radiation play in the adjuvant setting?

Dr Hensley: Because the risk for recurrence is so high, people have long wanted to offer some sort of adjuvant therapy, although wanting to offer something is one thing and proving that it helps is quite another. Radiation has been looked at in a randomized trial in which one half the women got pelvic radiation and the other half did not.[14] All of the patients in that trial had tumors that were confined to the uterus and had been completely removed by surgery. Eligible patients had a leiomyosarcoma, a stromal sarcoma, or carcinosarcoma.

In that somewhat mixed group of patients, the overall data showed that the addition of radiation to the pelvis after the removal of a tumor confined to the uterus did not increase overall survival. In the group of patients with uterine leiomyosarcoma, the addition of radiation did not decrease the risk for local recurrence. On the basis of that randomized trial,[14] we do not usually recommend adjuvant pelvic radiation for a tumor confined to the uterus.

But adjuvant chemotherapy may prove a stronger possibility. Because we have drug regimens that work in the metastatic setting, researchers postulate that use of those drugs in the adjuvant setting may help to prevent recurrence.

We conducted a phase 2 trial of adjuvant chemotherapy in women with uterine-confined, high-grade leiomyosarcoma. Because our study[15] had no control group, we compared the results for progression-free survival with the outcomes observed in a previous randomized trial of adjuvant radiation therapy.[14] Although the progression-free survival data seemed very promising at year 2, we observed recurrences between years 2 and 3.

In the absence of a randomized, prospective trial, we couldn't say whether chemotherapy improves outcome in this disease. To answer this question, we are conducting an international, randomized trial of adjuvant chemotherapy vs observation for patients with completely resected, uterus-confined, uterine leiomyosarcoma. The trial is Gynecologic Oncology Group (GOG) 0277,[16] and it has a good probability of being the definitive trial for determining whether adjuvant chemotherapy improves survival outcomes in women with high-risk disease.

Medscape: Considering the rarity of the disease, what challenges do oncologists face in managing uterine leiomyosarcoma?

Dr Hensley: The good news is that given enthusiasm and effort, it is possible to conduct prospective clinical trials in rare diseases. We have done that in uterine leiomyosarcoma. Here at Memorial Sloan Kettering, we looked at a novel regimen for treating leiomyosarcoma after standard therapies, such as doxorubicin, had failed[17]; this study helped us to increase treatment options for patients with this disease. Our work investigating fixed-dose-rate gemcitabine plus docetaxel was successful in our phase 2 clinical trial.[17]

Subsequently, this regimen showed excellent response rates in two national phase 2 trials in uterine leiomyosarcoma,[18,19] and in a third randomized trial of gemcitabine/docetaxel vs gemcitabine[20] that was for patients with uterine leiomyosarcoma or other soft-tissue sarcoma. In that trial,[20] response rate, progression-free survival, and overall survival were superior among patients treated with gemcitabine/docetaxel. That body of work led to gemcitabine plus docetaxel being incorporated into the National Comprehensive Cancer Network guidelines as a standard approach for leiomyosarcoma and soft-tissue sarcomas.[21]

This experience with developing a novel treatment regimen for uterine leiomyosarcoma can raise hope that we can successfully study these rare diseases and move the field forward. Sometimes what we learn from rare cancers is applicable to other cancers, which is very exciting. The more we cooperate, the better. To that end, we have an international rare cancer initiative—a collaboration among the National Cancer Institute, the European Organisation for Research and Treatment of Cancer, Cancer Research UK, and a subgroup of the International Rare Cancers Initiative—focused on gynecologic sarcomas.[22] We aim to conduct cooperative, international trials to help us develop better treatments for these rare diseases.

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