Uterine Sarcomas
Carcinosarcomas and other uterine sarcomas are uncommon tumors, accounting for less than 4% of all cancers of the uterine corpus. Carcinosarcomas, the most common histologic subtype, demonstrate both epithelial and stromal differentiation. Endometrial stromal sarcomas and leiomyosarcomas are characterized by differentiation toward one or more stromal tissues. Leiomyosarcomas occur at an earlier age than do carcinosarcomas, with a plateau observed in middle age. There is strong epidemiologic evidence that prior exposure to pelvic irradiation may increase the risk for the development of uterine sarcomas. Generally, these tumors are characterized by aggressive growth, with early lymphatic or hematogenous spread. The overall survival rate is poor, with the majority of deaths occurring within 2 years of diagnosis.
Patterns of Spread
Lymphatic metastases are a significant route of spread for carcinosarcoma, with a reported incidence of 40% to 60% occurring with stage I disease. Leiomyosarcoma has a propensity for extra-abdominal spread, often involving the lungs. For carcinosarcoma, the initial site for recurrence after surgical resection is likely to be the pelvis or abdomen, whereas leiomyosarcomas tend to fail to recur distantly. In a prospective surgical staging trial by the GOG, the recurrence rate for early-stage carcinosarcoma was 53% and for leiomyosarcoma was 71%.
Treatment
Surgery
Surgery is the mainstay of treatment for uterine sarcomas. For carcinosarcoma, this usually consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy, with washings to be obtained for peritoneal cytology. The GOG prospective staging study reported a 17% incidence of nodal metastasis for this histologic subtype, so retroperitoneal nodes should be sampled as for poorly differentiated endometrial cancers. For patients with advanced/recurrent disease, aggressive surgical debulking does not appear to improve outcome.
Hysterectomy with oophorectomy is also standard therapy for uterine leiomyosarcoma. Retroperitoneal nodal sampling is not usually performed, because lymph node involvement is unusual. For late recurrences of leiomyosarcoma, surgery must be individualized. Five-year survival rates of 30% to 50% have been reported following pulmonary resection for lung metastases. Patients with unilateral metastases have a significantly better prognosis than those with bilateral disease. Local and regional recurrences may also be amenable to surgical resection of disease.
Hysterectomy with oophorectomy is the standard of care for patients with low-grade endometrial stromal sarcomas. Removal of the ovaries was thought to be critical, as these tumors tend to have very high concentrations of estrogen and progesterone(Drug information on progesterone) receptors and often respond to hormonal therapy. However, Li et al reviewed a multi-institutional experience and reported that bilateral salpingo-oophorectomy did not appear to affect time to recurrence or overall survival. Retention of ovarian function may be an option for premenopausal women with low-grade endometrial stromal sarcomas. Because these tumors have a tendency to spread via the lymphatics, resection of all disease, especially extension into the parametrium, should be attempted. This approach may require radical hysterectomy.
Adjuvant irradiation
Pelvic recurrence is a pattern of failure for most uterine sarcomas; isolated pelvic recurrences are uncommon. Adjuvant irradiation can decrease local recurrence, but there is no evidence that it improves survival. Patients will often experience distant recurrence and treatment failure. Pelvic irradiation may be indicated for improvement of quality of life, however, because pelvic recurrence can be associated with pain, bleeding, and intestinal obstruction.
Radiotherapy
In a nonrandomized prospective GOG study, patients with stages I and II mixed mesodermal sarcomas and leiomyosarcomas had fewer pelvic recurrences following irradiation than did patients who did not undergo pelvic irradiation. No difference in overall or disease-free survival was noted.
Several retrospective reports have suggested improved pelvic control rates following pelvic irradiation for stages I and II uterine sarcomas. A randomized trial from the EORTC demonstrated that patients with carcinosarcoma randomized to receive pelvic radiation compared with no adjuvant treatment benefited from pelvic radiation, with decreased local failures but no survival improvement. Patients with leiomyosarcoma did not demonstrate any benefit with the addition of pelvic radiation.
GOG-0150 was a randomized study of patients with stages I–IV carcinosarcoma of the uterus with less than 1 cm of residual disease and no extra-abdominal spread. Patients were treated with either cisplatin(Drug information on cisplatin) (20 mg/m2/day for 4 days) plus ifosfamide(Drug information on ifosfamide) (1.5 g/m2/day for 4 days every 3 weeks for 3 cycles) or WAI to a total dose of 3,000 cGy, and the pelvis was treated to a total dose of 4,980 cGy. The abdomen received 150 cGy per fraction, with 5 fractions per week. The pelvis was boosted an additional 11 fractions at 180 cGy per fraction. The study tested whether patients treated with systemic treatment or locoregional treatment differ in progression-free interval, survival, and failure patterns. There were 105 patients in the WAI cohort and 101 in the chemotherapy cohort, respectively.
Of 206 study patients, there were 112 total recurrences (54%), with 60 (57%) in the radiotherapy arm and 52 (51%) in the chemotherapy treatment arm. Although patients may have had several different sites of failure, there were more vaginal failures in the chemotherapy group (10%) than in the WAI group (4%). However, there were more abdominal relapses in the WAI arm (28%) than in the chemotherapy cohort (19%). Pelvic and distant failures were essentially the same. Although acute toxicities of anemia and neuropathy were more frequent in the chemotherapy arm, there were more severe grade 3/4 gastrointestinal late effects in the WAI group, and two patients died as a direct result of radiation hepatitis. The estimated probability of surviving 5 years was 35% vs 45% for WAI vs chemotherapy. After adjusting for stage and age, there was no definite survival advantage but rather a trend favoring chemotherapy. The estimated death rate was 29% lower for chemotherapy patients than for WAI patients (hazard ratio [HR] = 0.712; 95% CI, 0.484–1.048; P = .085, two-tail test).
GOG-0150 has shown that adjunctive chemotherapy has less toxic long-term side effects and is more likely than radiotherapy to improve survival for these patients. Because chemotherapy did not reduce the risk of vaginal relapses, less-toxic vaginal brachytherapy with chemotherapy would be an appropriate experimental arm for future adjuvant therapeutic trials in this group of patients.
Chemotherapy
There is no proven role for adjuvant chemotherapy in stage I disease following complete surgical resection. A GOG study looking at adjuvant doxorubicin(Drug information on doxorubicin) vs no further therapy showed no differences in recurrence rate, progression-free survival, or overall survival. GOG0117 showed that adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus was tolerable. That combination was then compared with WAI in GOG-0150 (described in detail above), which showed a trend in survival favoring those treated with that chemotherapy combination.
For patients with advanced/recurrent disease, single-agent chemotherapy or combination chemotherapy can be used with a palliative intent. For carcinosarcomas, ifosfamide or paclitaxel(Drug information on paclitaxel) appears to be the agent of choice. Because GOG0108 showed that ifosfamide plus cisplatin had no greater progression-free interval or survival than ifosfamide alone, GOG0161 randomized patients to receive ifosfamide (at 2 g/m2 for 3 days every 3 weeks for 8 cycles) vs ifosfamide (1.6 g/m2 for 3 days) plus paclitaxel (135 mg/m2 by 3-hour infusion on day 1 repeated every 3 weeks for 8 cycles). There was a survival advantage for combination chemotherapy (13.5 months vs 5.8 months).
Doxorubicin has traditionally been used for leiomyosarcomas. Hensley et al reported that the combination of gemcitabine(Drug information on gemcitabine) plus docetaxel(Drug information on docetaxel) produced a 36% response rate in leiomyosarcoma. Hormonal agents, specifically progestins, are the treatment of choice for advanced/recurrent endometrial stromal sarcomas.
