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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 117Gynecologic Sarcomas

, MD, , MD, and , MD.

Even though the female pelvis is richly endowed with blood vessels, connective tissue, and müllerian elements, sarcomas (including melenchymal and mixed epithelical/mesenchymel malignancies) of the vulva, vagina, cervix, uterus, and ovaries account for less than 1.5% of the cancers of these organs. The most common site for sarcoma in the female pelvis is the uterus, but only 3% of uterine cancers are sarcomas.1 Because of the infrequent occurrence of sarcomas, classification of these cancers was a taxonomic dilemma until Ober in 1959 proposed a classification that became the basis from which modern modifications have been derived. A detailed classification, adapted from Kempson and Bari,2 and a functional classification, developed by the Gynecologic Oncology Group (GOG), are presented in Table 117.1.

Table 117.1. Classification of Uterine Sarcomas.

Table 117.1

Classification of Uterine Sarcomas.

The most widely referenced epidemiologic study on uterine sarcomas was conducted by Harlow and co-workers,1 who analyzed the population-based registries comprising the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute from 1973 to 1981. The incidence rate per million women per year was 8.2 for malignant mixed müllerian tumors (MMMT), 6.4 for leiomyosarcoma (LMS), 1.8 for endometrial stromal sarcoma (ESS), and 0.7 for unclassified sarcomas. The risk of sarcoma is higher in African American women than in Caucasians, and the risk of MMMT increases sharply with age.

Epidemiologic risk factors for uterine sarcoma have not been clearly defined, except for prior radiation exposure. An association has been observed between exposure to radiation and development of uterine sarcomas, most of which are MMMT. Although the relative risk is estimated at 5.4,3 the percentage of patients with uterine sarcomas who have previously undergone radiation therapy ranges from 12 to 30%.4 No other epidemiologic factors examined in the literature have consistently demonstrated an effect on the risk of developing uterine sarcoma.

The uterus is the most common site of gynecologic sarcomas. Uterine sarcomas can be assigned to two general categories: ESS, and MMMT, derived from the endometrial compartment, and leiomyo sarcomas of the myometrium. The myometrial group includes primarily LMS and MMMT, either homologous or heterologous. The homologous tumors include carcinoma plus a sarcoma differentiating toward tissues indigenous to the uterus, and the heterologous tumors include carcinoma plus sarcoma resembling tissue from some extrauterine source (bone, cartilage, striated muscle) with or without homologous elements. Traditionally, authors have reported that MMMT and LMS each account for 35 to 40% of uterine sarcomas, with ESS accounting for 10 to 15% and other sarcomas composing 5%. However, in one of the most detailed clinicopathologic evaluations of clinical stage I and II uterine sarcomas prospectively performed, the GOG in an analysis of 453 patients found that 66% had MMMT, 13% had LMS, and the remaining 21% were predominantly adenosarcomas and ESS.5

The reason for this apparent change in the ratio of the two most frequently diagnosed uterine sarcomas is unclear; however, several smaller series reported in the past decade have noticed this trend in the histologic analysis performed. The significance of the GOG studies is that a single group of referee pathologists reviewed all of the pathologic material, and surgeons followed common surgical guidelines so that all patients met strict criteria for the acceptability of both the surgical procedure and the adequacy of pathologic specimens submitted.

One of the pitfalls in diagnosing sarcomas is the variability in threshold for distinguishing between atypical benign tissues and clearly malignant tissues. In general, it is reasonable to conclude that if a mesenchymal tumor of the uterus has 1 to 4 mitoses per 10 high-power fields, the metastatic potential is virtually nil. If there are 10 or more mitoses per 10 high-power fields, the risk for recurrence is high, irrespective of the presence of atypia. If there are 5 to 9 mitoses per 10 high-power fields without atypia, the risk of recurrence or metastasis is moderate, but if atypia is also present, the patient should be considered to have a sarcoma.

It is important to realize, however, that there are important exceptions to these generalizations. For example, mitotically active smooth muscle tumors without atypia occuring in young women usually behave in a benign manner. Conversely myxoid leiomyosarcoma, often have deceptively low mitotic counts.

Clinical Profile

Uterine Endometrial Stromal Tumors

Patients with endometrial stromal tumors tend to be perimenopausal and ordinarily present with irregular vaginal bleeding. If the lesion is small, pain may be absent, but on pelvic examination tumor tissue may be seen protruding through the cervical os, because the tumor originates in the endometrium and may grow large without penetrating through the uterine wall. The diagnosis is made by endometrial sampling, which should be done liberally to explain vaginal bleeding. Among the endometrial stromal tumors is the endometrial stromal nodule, usually an expansile, noninfiltrating, unifocal lesion with low mitotic activity and low virulence. Removal of the nodule has resulted in cure, without further therapy. Endolymphatic stromal myosis (ESM) is a low-grade stromal sarcoma having a wormlike infiltrative pattern that extends beyond the uterus in approximately 40% of patients. It recurs in approximately 50% after surgical removal but is indolent in its course, often treated by repeated excisions over a long course of months or years. There is evidence for radiosensitivity6 and hormone sensitivity, with the observation that oophorectomy alone can control the disease in a subset of patients.7 High grade ESSs, on the other hand, are more aggressive cancers. Patients survive well when the tumors are small and confined to the uterus at the time of initial treatment; however, poorly differentiated lesions or those with extrauterine extension are usually lethal.

Mixed Tumors

The incidence of MMMT begins to increase at approximately 50 years of age and does not plateau until after age 75 years. The presenting complaints may include vaginal bleeding, heavy discharge, abdominal pain, and sometimes an increase in abdominal girth. The diagnosis is made more frequently by endometrial sampling than in the case of LMS because the latter disease often does not involve the endometrial cavity. Other than previous exposure to ionizing radiation, there is no unusual risk factor for patients with uterine sarcomas.

Uterine Myometrial Tumors

LMSs commonly occur during the fourth and fifth decades of life, with a peak incidence at 45 years of age, after which there is a gradual decline in incidence until the eighth decade. The lesion is frequently associated with benign leiomyomas, although among leiomyomas, sarcoma is found less than 1% of the time. There is considerable debate over whether the lesion “develops” from a benign leiomyoma or occurs independently. Ferenczy and co-workers8 were unable to demonstrate a developmental relationship, whereas Spiro and Koss9 found intermediate changes in leiomyomas and indicted these benign lesions in 50% of the cases of LMS they studied. Often LMSs are discovered by chance at the time of myomectomy or hysterectomy. Davids10 who removed 5 sarcomas in a series of 1,150 myomectomies, observed that the 5 patients were well after 5 years and that 3 of them subsequently became pregnant. No mention was made of virulence indices in the pathologic examination of these tumors.

Diagnosis

The most common presenting symptom for all types of uterine sarcomas is abnormal vaginal bleeding that occurs in 75 to 95% of patients. Pelvic pain occurs frequently in patients with uterine sarcomas and may be accompanied by discharge and aborting tissue. Despite the above signs and symptoms, the diagnosis of uterine sarcoma is frequently made only at the time of hysterectomy for a presumed benign condition.11 In most cases, preoperative endometrial sampling is not a reliable method for making the diagnosis of uterine sarcoma.11 Patients with MMMT who have bleeding usually have an endometrial biopsy that reveals the poorly differentiated component of the tumor. However, for LMS and ESS, preoperative dilatation and curettage of the uterus misses the diagnosis in at least 40 and 20% of cases, respectively.11–13

Radiography may be useful in diagnosing uterine sarcomas. Computed tomography can be used to identify patients with extrauterine spread and magnetic resonance imaging can be used to assess depth of myometrial invasion. The role of ultrasonography is currently being studied by several investigators.14 Kurjak and co-workers evaluated the role of transvaginal color Doppler in differentiating uterine sarcomas from leiomyomas.14

Sarcoma-Like Variants

There are four pathologic entities that are abnormal forms of leiomyoma and should be distinguished from uterine sarcomas.

Benign metastasizing leiomyoma is a rare entity in which histoligically benign uterine smooth muscle is found in extrauterine deposits, often distant from the uterus, especially in lymph nodes and lungs.15 Whether the nodules are metastic or multifocal remains to be resolved. Several observers have noted the hormone dependence of these deposits. After hysterectomy with bilateral salpingo-oophorectomy the nodules often regress, and if they interfere with performance they can be individually resected.

Intravenous leiomyomatosis is the growth of histologically benign smooth muscle into venous lumina. Although the pattern is often wormlike, it should not be confused with endolymphatic stromal myosis, which is located primarily extravascularly. Although intravenous leiomyomatosis is histologically benign, deaths have been reported from very long tumor extensions occupying the vena cava and the heart.16 In this condition, the extension of tumor is contiguous, unlike the widely disparate deposits in benign metastasizing leiomyoma.

Leiomyomatosis peritonalis disseminata is a rare condition in which nodules composed of benign smooth muscle are densely distributed throughout the peritoneal cavity. Much of the peritoneal surface may be occupied by nodules ranging in size from a few millimeters to several centimeters. Treatment requires removal of as much disease as possible and reversal of any estrogenic stimulation, either by removing the ovaries or by treatment with antiestrogen regimens.

Epithelioid leiomyoma or leimyobastoma denotes a rare group of benign smooth muscle tumors that are formed by round cells with clear cytoplasm. They are less well circumscribed than, and occasionally lack the whorled, cut surface and the discrete borders of a typical leiomyoma. Usually, their mitotic rate is less than three mitoses per 10 high-power fields, and the rate of recurrence or metastasis is low.17

Patterns of Spread

Uterine sarcomas can spread by lymphatic and hematogenous routes,18 as well as by local extension and peritoneal spread.19 Several studies have addressed the metastatic pattern of uterine sarcomas. Chen20 examined nodal metastases in 20 patients with clinical stage I uterine sarcomas. Fourteen patients had MMMT, 4 had LMS, and 2 had ESS. Of 9 patients (45%) with lymph node metastases, 6 had both para-aortic and pelvic node involvement, and 3 had only pelvic node involvement. Among ESS and MMMT high frequency of association was observed between nodal spread and deep myometrial invasion. Other sites of extrauterine spread were the ovary (2 patients) and the serosa of the uterus (1 patient). DiSaia and co-workers21 reported on 28 patients with clinical stage I and II carcinosarcoma who underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node sampling. Ten (35%) of the 28 patients had positive pelvic nodes; 4 of these 10 patients also had para-aortic node metastasis (14.5%). In every instance of nodal involvement, the myometrial invasion was to the middle or outer third.

Rose and co-workers18 studied the autopsy findings of 73 patients with uterine sarcoma, including 43 patients with MMMT, 19 with LMS, 9 with ESS, and 2 with ESM. The peritoneal cavity and omentum were the most frequently involved sites (59%), followed by the lung (52%), pelvic (41%) and para-aortic (38%) lymph nodes, and liver parenchyma (34%). Of note, the presence of lung metastasis was not associated with pelvic or para-aortic nodal metastasis or intraperitoneal disease. In another review of autopsy findings, Fleming and co-workers19 reviewed the records of 22 patients treated for uterine sarcoma, including 11 MMMT, 6 ESS, and 5 LMS. Fifty-nine percent had lymph node involvement, and 45% died with disease limited to the pelvis and abdomen. The most common site of disease above the diaphragm was the lung. The authors reviewed autopsy findings of 58 patients from previous reports in the literature, and found a similar incidence of nodal involvement (57%) and disease limited to the pelvis and abdomen (31%). In addition, 65.5% of patients had abdominal as well as distant metastases.

Recently, Goff and co-workers11 examined nodal metastases from uterine LMS and ESS. Retroperitoneal lymph node sampling revealed lymph node metastases in 4 of 15 women with LMS, and in each instance, there was also disseminated intraperitoneal disease. Seven of 10 women with ESS had lymphadenectomies, and none had positive nodes.

Prognostic Factors and Prognosis

Prognostic factors differ for the three major types of uterine sarcomas. Majors and co-workers reported the GOG clinicopathologic study of clinical stage I and II uterine sarcoma, which included 59 patients with LMS and 301 patients with MMMT.5 Of the 453 patients eligible for analysis, 430 underwent complete surgical staging that included lymphadenectomy. The progression-free interval was measured, and all analyses of prognostic features were done separately for patients with MMMT and those with LMS. The median survival for MMMT (homologous) was 62.6 months, for MMMT (heterologous) 22.7 months, and for LMS 20.6 months. The overall recurrence rate was 56%.

In patients with LMS, lymph vascular space involvement and involvement of the cervix and isthmus were common, whereas lymph node metastases, adnexal metastases, and positive peritoneal cytology were infrequent findings. The only surgicopathologic finding that correlated with progression-free interval was the mitotic index. Whereas there were no treatment failures among the three women who had less than 10 mitoses per 10 high-power fields, 61% of women with 10 to 20 mitoses per 10 high-power fields and 79% of women with greater than 20 mitoses per 10 high-power fields developed recurrences. Fewer mitoses were also associated with longer survival. Other investigators have confirmed these results.22,23

In contrast to patients with LMS, surgicopathologic factors of MMMT that related to progression-free interval included adnexal spread, lymph node metastasis, histologic cell type (heterologous versus homologous), and grade of sarcoma. Of note, patients with MMMT had high rates of nodal and adnexal metastases as well as positive peritoneal cytology. Pelvic nodes were involved twice as often as aortic nodes (15 versus 7.8%), and both nodal groups were involved in 5% of the patients.

Nonuterine Gynecologic Sarcomas

See Fig. 117.1

Figure 117.1. Management of nonuterine gynecologic sarcomas.

Figure 117.1

Management of nonuterine gynecologic sarcomas.

Vulva

Fewer than 300 patients with vulvar sarcoma have been described in the literature. Leiomyosarcoma, rhabdomyosarcoma, and fibrosarcoma are the most frequently diagnosed vulvar tumors. The clinical behavior of these tumors is related to their grade, mitotic count, histology, and stage. For the lowest-grade tumors, wide local excision should suffice. However, for the more aggressive histologic patterns, radical vulvectomy with lymphadenectomy followed by cytotoxic chemotherapy should be considered, although the role of adjuvant chemotherapy has not been studied in these tumors.

Vagina

Leiomyosarcoma of the vagina occurs in the same age groups as does leiomyosarcoma of the uterus. Although this tumor is highly virulent, survivors are among those treated by hysterectomy, oophorectomy, and vaginectomy. Embryonal rhabdomyosarcomas, formerly termed sarcoma botryoides, are actually MMMT of the vagina. These tumors occur most frequently in children and have a typical grape-cluster-like appearance. The disease was once uniformly fatal, provoking radical extirpative surgery that resulted in exenteration for young girls. Various multi-drug cytotoxic chemotherapy regimens with or without radiation therapy have replaced primary exenteration, and cure is now expected. Radical surgery is reserved for failures of nonsurgical treatment.

Ovary

Most types of sarcomas described in the vagina, vulva, or uterus have been found in the ovary as well. The diagnosis of ovarian sarcoma is infrequently made prior to laparotomy. The surgical treatment is identical to that for epithelial ovarian cancers. During the past decade, MMMT of the ovary has been described with increasing frequency.24,25 Survival is better for patients with early-stage disease and those whose tumors have homologous stromal elements. In one group of patients treated between 1977 and 1988,25 the median survival time for patients receiving doxorubicin and cisplatin chemotherapy after cytoreductive surgery was 16 months. Sixty-two percent were alive at 12 months and 31% at 24 months. Although responses were noted in 85% of treated patients, treatment failed in half of these. Serum CA-125 levels accurately reflected tumor presence in 82% of the tested patients. Although the cytotoxic chemotherapy employed produced a response, survival from these virulent tumors was poor.

Fallopian Tube

The fallopian tube is the least frequent site of primary sarcomas in the gynecologic tract. From reports in the literature it would seem that carcinoma of the fallopian tube, itself an unusual entity, is more than 20 times more common than fallopian tube sarcoma. The most common histologic type is MMMT.26 In Imachi and colleagues’ 1992 review, there were 39 patients with MMMT of the fallopian tube.26 Clinical features and difficulty in diagnosis are identical to those for patients with adenocarcinoma of the fallopian tube. Half the patients had homologous elements and half had heterologous components. The surgical approach is the same as that used for ovarian or fallopian tube epithelial carcinoma, and postoperative treatment has usually included cytotoxic chemotherapy. Combinations of cyclophosphamide, doxorubicin, and cisplatin have been effectively applied as has the combination of vincristine, doxorubicin, and cyclophosphamide.27 Long-term survivors have been reported but are uncommon.

Surgical Treatment

The initial therapy for sarcomas of the gynecologic tract is surgical (Fig. 117.2). Patients with uterine sarcoma require total abdominal hysterectomy and careful staging. In patients with MMMT limited to the uterus by pathologic staging, the cytologic presence of malignant cells in the peritoneal washings is a poor prognostic factor.28

Figure 117.2. Management of uterine sarcomas.

Figure 117.2

Management of uterine sarcomas. D & C = dilation and curettage; CT = computed tomography. Adapted from Morrow and Curtain.

The ovaries should be retained in premenopausal patients with LMS, since it appears to improve their prognosis.13,29,30 However, a bilateral salpingo-oophorectomy should be performed in all other patients, including those with low-grade ESS, since these tumors may be hormone dependent or responsive and they have a propensity for extension into the parametria, broad ligament, and adnexal structures.

For MMMT, a high percentage of patients with clinical stage I or II disease are upstaged at the time of laparotomy;31,32 thus it appears reasonable to surgically stage these patients. There is a paucity of data regarding the role of lymph node sampling in patients with LMS and ESS, but it appears that almost all patients with these sarcomas who have lymph node metastases also have evidence of intraperitoneal disease spread.33

Unlike other gynecologic malignancies, there is a role for thoracotomy in patients with uterine sarcoma metastatic to the lung. Levenback and co-workers34 reviewed 45 patients whose pulmonary metastases from uterine sarcoma were resected at Memorial Sloan-Kettering Cancer Center, the majority of which were LMS (84%). Most lesions were unilateral (71%), 70% were greater than 2 cm, and one-half were isolated lesions. The mean survival of patients with unilateral disease (39 months) was significantly greater than patients with bilateral disease (27 months). No single risk factor was identified that could exclude an individual patient from consideration for pulmonary resection. There is also a role for surgery in the treatment of local and regional recurrences of uterine sarcomas. In the M. D. Anderson series of 120 patients with MMMT reported by Spanos and co-workers,35 67 patients developed recurrent disease. In the 6 patients with lesions deemed suitable for resection (1 loco-regional; 2 pulmonary, and 3 abdominal), 5 complete and partial responses occurred for an overall response rate of 83%. Recurrent or metastatic low-grade ESS may also be amenable to surgical excision of pelvic disease or pulmonary metastases.

The International Federation of Gynecology and Obstetrics (FIGO) staging criteria for corpus cancer is commonly used for uterine sarcomas.36 This is a surgical staging system.

Postsurgical Therapy for Gynecologic Sarcomas

Although complete surgical removal is the ideal initial therapy for patients with sarcoma of the gynecologic tract, there is no randomized study proving that surgical cytoreduction influences overall survival for patients with advanced or recurrent disease. Similarly, the therapeutic benefit of lymphadenectomy has not been proven but is rational. For patients with sarcoma of the uterus or ovary, no formal trial has evaluated the role of lymphadenectomy in addition to hysterectomy and bilateral salpingo-oophorectomy.

For patients with uterine sarcoma, there is no definitive evidence from prospective trials that adjuvant therapy of any type leads to overall improvement in survival. To review the currently understood role of radiotherapy and chemotherapy in sarcomas, LMS will be separated from the remaining homologous and heterologous MMMT because the patterns of relapse for the former are somewhat different from those of the latter group.

Hormone Therapy

Receptors for estrogen and progesterone are identified in patients with uterine sarcoma.37,38 Sutton and co-workers studied 43 patients with various uterine sarcomas and found estrogen receptors in 55% of the tumors and progesterone receptors in 55%.37 The median values were much lower than those found in consecutively tested endometrial adenocarcinomas and breast carcinomas from the same laboratory. The presence of receptors was not influenced by stage or grade, but levels were much higher and more prevalent in patients with ESS of low grade, and this group of tumors frequently responds to progestational hormone treatment. For the other sarcomas, receptor status did not affect response to cytotoxic agents, but the presence of estrogen receptors seemed to be associated with longer survival. The presence of estrogen or progesterone receptors did not correlate with response to hormonal therapy consisting of progestational therapy with or without tamoxifen.

Radiation Therapy for Leiomyosarcoma

In contrast to other sarcomas, patients with LMS confined to the uterus appear to have a dominant pattern of failure outside the pelvis and abdominal cavity. In three series in which the site of first recurrence was documented, 14 (28%) of 49 patients developed pelvic or abdominal recurrence, compared with 32 (65%) of 49 patients whose first recurrence had some component of distant disease.39–41 Thus, in LMS, although the rate of failure in the pelvis is not insubstantial, little is to be potentially gained by delivering pelvic irradiation as a postoperative adjuvant treatment, insofar as two-thirds of patients have some component of distant disease at first recurrence.

Although pelvic radiation has been used historically as an adjunct to surgery, many therapists have abandoned its use in patients with LMS because of the dominant pattern of distant failure, and they reserve radiation treatment for isolated pelvic relapse only. This would appear to be a rational decision because it is highly unlikely that pelvic irradiation contributes to overall survival from LMS.

Radiation Therapy for Malignant Mixed Müllerian Tumors

Historically, pre- or postoperative pelvic irradiation has been used as an adjunct to surgery for MMMT. Many retrospective reviews illustrate this common usage.35,42–46 Often the criteria for selecting patients for pelvic irradiation after surgery have not been stated, although they probably reflect an investigator bias toward the use of radiation therapy for patients deemed to be at high risk for relapse. Several studies have identified adverse prognostic factors for MMMT,32,42,47 however, no report has systematically evaluated the role of adjunctive radiation therapy related to these risk factors in mixed müllerian tumors.

Similarly, there has been no randomized comparison of the influence of adjuvant pelvic irradiation on loco-regional control or survival versus that achieved with surgery alone. The GOG is currently conducting a phase III study of whole abdominal radiotherapy versus ifosfamide/mesna with cisplatin in patients with optimally debulked stage I-IV MMMT (protocol #150). The benefit of adjuvant radiotherapy in the treatment of MMMT has not been demonstrated in randomized studies. The major problem in evaluating this question is the lack of comparability of risk factors for relapse in nonradiated and irradiated patients because those irradiated may represent a group at higher risk for recurrence. However, the pelvic recurrence rate in MMMT justifies the need to employ adjuvant therapy for loco-regional control. Several reports have documented the pattern of recurrences in patients with all types of stage I or II sarcomas. For MMMT, the pelvic recurrence rate was 56%, whereas the distant metastasis rate was 45%. This represents a significantly higher relative risk for pelvic recurrence than that seen in patients with LMS.35,42–44,48 It also demonstrates that surgery alone, even for disease apparently confined to the uterus, is inadequate for control of disease in the pelvis.

Some, but not all studies have shown benefit from postoperative irradiation,49,50 especially in local control.46,51–55 However, few studies show that increased local control rates have an effect on overall survival.42,55,56 Cumulative rates of distant metastases in series of patients treated with or without adjuvant pelvic irradiation are similar, in the order of 35%.42,43,46,48 Adjuvant irradiation has not produced a detectable reduction in rates of distant metastasis. More recently, Knocke and co-workers57 observed that local control could be achieved in 83.4% of patients and distant control in 70.8%. The overall survival rate was 52.9% and the disease-specific survival rate was 57.7%, which is high compared with the majority of reports in the literature.

In a study of the GOG conducted between 1973 and 1982, patients with stage I or II uterine sarcomas, including LMS (48 patients), MMMT (95 patients), ESS (10 patients), and unclassified tumors (4 patients), were randomly assigned to receive adjuvant doxorubicin or no chemotherapy following surgery.46 The use of adjuvant pelvic radiation therapy was not controlled but was left to investigator discretion, and the study was not stratified for the use of radiation therapy. A subset analysis of this study was conducted by Hornback and co-workers46 and demonstrated a reduction in pelvic recurrence rates attributable to the use of adjunctive pelvic irradiation. The data must be interpreted with some caution, however, because this was a nonrandomized comparison.

The morbidity associated with pelvic recurrence in uterine sarcomas may be substantial; therefore, it is reasonable to offer adjuvant pelvic irradiation to patients with MMMT to improve loco-regional control rates. The doses of radiation have not been standardized; however, it is probable that doses should be at least 50 Gy, fractionated over 5 weeks. Several reports, especially that from the M.D. Anderson Cancer Center, suggest that in a significant proportion (approximately 30%) of patients, upper abdominal metastases develop, either in nodes or on peritoneal surfaces, without dissemination beyond the peritoneal cavity.19,35,58 Unfortunately, a detailed examination of factors predicting for disease recurrence confined to the abdomen has not been performed. Because radiation therapy is effective in reducing recurrence of disease in the pelvis and may be more effective than any currently available chemotherapeutic agent, it would be rational to explore the role of whole abdominopelvic irradiation in patients whose disease is likely to be confined to the peritoneal cavity and retroperitoneal lymph nodes.

Primary pelvic irradiation has been employed rarely in patients with sarcoma deemed inoperable. The possible additional utility of intracavitary irradiation must be evaluated because radiation dose distribution may be inadequate if the uterus is bulky. Literature reports suggest that in approximately one-half or two-thirds of patients, pelvic disease could be controlled with standard fractionated irradiation; a small proportion of patients are cured with such treatment.35,42–44

Finally, radiation may be useful as a palliative measure for recurrent or uncontrolled pelvic tumor causing pain or bleeding.

Chemotherapy

Although cytotoxic chemotherapy has been applied to patients with sarcomas in multiple sites in the gynecologic tract, the predominant application has been for patients with uterine sarcomas. Two characteristics of uterine sarcomas increase the likelihood that systemic therapy will be required: a recurrence rate of at least 50% even in stage I disease, and a tendency to recur at distant sites. Nevertheless, the amount of meaningful data on the use of systemic therapy is limited by the low incidence of these lesions. The results of studies of the GOG, however, have provided a rationale for the selection of systemic therapy. Studies by the GOG first identified the differential sensitivity of MMMT and LMS to drug therapy.59 Because these two cell types respond differently to chemotherapy, they will be discussed separately.

Single-Agent Therapy

Several drugs have been studied as single-agent therapy in advanced or recurrent MMMT and/or LMS, including cisplatin,60–63 ifosfamide,64,65 doxorubicin,59,66 etoposide,67–70 mitoxantrone,71 piperazinedione,72 aminothiadiazole,73,74 azirdinylbenzoquinone,75,76 paclitaxel,77 and topotecan.78

For patients with MMMT, there are two clearly active agents: ifosfamide and cisplatin (Table 117.2). Ifosfamide is the most active single agent in the treatment of advanced or recurrent MMMT of the uterus. Sutton and co-workers64 conducted a phase II study of ifosfamide (1.5 g/m2/d for 5 days every 4 weeks) and mesna in 30 patients with advanced or recurrent MMMT who had no prior chemotherapy. In 28 patients available for response, 5 patients had complete responses (17.9%) and 4 patients had partial responses (14.3%) for a total response rate of 32.2%. However, the response duration ranged from 1.4 to 8.6 months with a median response duration of only 3.8 months (see Table 117.2).

Table 117.2. Single-Agent Activity in Uterine Sarcomas.

Table 117.2

Single-Agent Activity in Uterine Sarcomas.

Cisplatin also appears to have significant activity.60 In patients who had previously received chemotherapy, cisplatin, 50 mg/m2 produced an 18% response rate. Of 28 patients available for evaluation, 2 complete responses and 3 partial responses were observed. The duration of the two complete responses was 14 and 16 months, and the median duration of the partial response was 3 months. Within this population, 42.9% had received radiation therapy, and 89.3% had received prior therapy with doxorubicin or a doxorubicin-containing combination. This prior chemotherapy history is significant, given the fact that second-line chemotherapy for sarcomas has been notably unsuccessful. In patients who had not previously received chemotherapy, the same response rate of 19% was observed among a larger group of 63 patients treated with the same dose and schedule.61 Five complete responses and 7 partial responses were observed. The median duration of response was 6.6 months; the median survival was 9.3 months for complete responders and 16.8 months for partial responders. In a separate phase II trial, a higher dose, ranging from 75 to 100 mg/m2 every 3 weeks produced 1 complete and 4 partial responses among 12 patients (42%) who had not previously received chemotherapy.62 The small number of cases and the lack of a randomized trial permit no conclusions to be drawn about the merits of the higher dose.

Of the single agents that have been tested in patients with LMS (see Table 117.2), doxorubicin is the most active. In the two GOG phase III trials comparing doxorubicin-based chemotherapy in combination with dimethyl triazenoimidazole carboxamide (DTIC)59 or cyclophosphamide79 in advanced uterine sarcomas, response rates of 25% and 13%, respectively, were observed in patients with LMS treated with doxorubicin alone. Patients with LMS also had a significantly longer survival time than the other histologic cell types studied (12.1 versus 6.0 months). Ifosfamide, 1.5 g/m2/d for 5 days every 3 to 4 weeks, exhibited moderate activity, with 6 responses among 35 patients.65

There is little data in the gynecologic literature regarding the use of chemotherapy for ESS. The GOG conducted a phase II study of ifosfamide in women with metastatic ESS previously unexposed to chemotherapy.80 Of 21 evaluable patients, 3 patients experienced complete tumor responses, and 4 had partial responses for an overall response rate of 33.3%. Other agents have also been found to be active in the treatment of ESS including doxorubicin,11,13 the combination of vincristine, actinomycin D, and cyclophosphamide (VAC),13 the combination of mitomycin and vinblastine,13 chlorambucil,81 and the combination of cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC).81

In summary, two agents active against MMMT of the uterus have been identified: ifosfamide and cisplatin. In LMS, doxorubicin and ifosfamide appear to have significant activity.

Combination Therapy

Meaningful evaluation of combination chemotherapy necessitates randomized trials. The two such studies completed to date form the basis for current conclusions regarding the role of chemotherapy.

In the first randomized trial, patients with advanced (stage III or IV or recurrent) uterine sarcoma received either doxorubicin or doxorubicin plus DTIC (Table 117.3).59 Although no significant differences between the two regimens were observed, conclusions from the trial were limited by the fact that the study being designed before differences in response to chemotherapy for LMS and MMMT were understood, the total patient population supplied an insufficient number of each histologic type to permit subset analysis.

Table 117.3. Randomized Trials of Chemotherapy in Advanced or Recurrent Uterine Sarcomas.

Table 117.3

Randomized Trials of Chemotherapy in Advanced or Recurrent Uterine Sarcomas.

The second randomized trial studied doxorubicin with or without cyclophosphamide (see Table 117.3) and was closed prior to completion of original accrual goals because, on the basis of early data, the likelihood of identifying a difference in the two treatment regimens was extremely small.78 The overall response rate was the same for doxorubicin with or without cyclophosphamide (19.2% total response rate). Thus no benefit was demonstrated by adding cyclophosphamide to doxorubicin. When the data were analyzed by cell type, 3 of the 20 patients with MMMT had complete responses.

With recognition of the difference in response between LMS and MMMT, randomized trials had to consider the two major histologic types as distinct entities requiring separate studies. A third phase III trial, completed in July, 1996, compares ifosfamide with and without cisplatin in patients with advanced or recurrent MMMT.82 Ifosfamide was given in a dose of 1.5 g/m2/d for 5 days every 3 weeks for eight courses, with mesna uroprotection. In the combination arm, cisplatin was added at 20 mg/m2 for 5 days. Early in the study, the dose of the combination regimen was decreased by 20% because of toxicity. Overall, 54% of patients treated with the combination regimen and 36% of patients treated with ifosfamide alone responded to therapy. Response duration and survival are currently under analysis. Studies of LMS continue to focus on the identification of active drugs in phase II trials.

As discussed previously, the GOG demonstrated no benefit to the addition of either cyclophosphamide or DTIC to doxorubicin in advanced uterine sarcomas.59,79 The GOG conducted a phase II study of doxorubicin in combination with ifosfamide/mesna in previously untreated patients with advanced or recurrent uterine LMS.83 Of 33 patients, there was 1 complete response and 10 partial responses. Although the overall response rate was 33.3%, the toxicity was severe, with 13 patients developing grade 4 neutropenia and 2 patients developing grade 4 cardiotoxicity.

The GOG recently reported on the results of a phase II trial of hydroxyurea, DTIC, and etoposide in the treatment of advanced or recurrent uterine LMS.84 Of 38 evaluable patients, there were 2 complete responses and 5 partial responses for an overall response rate of 18.4%; 6 of the 7 responders had disease outside the pelvis. The response duration was 12.1 months. Thus, this combination had moderate activity in the treatment of advanced or recurrent uterine LMS.

Adjuvant Therapy for Limited Disease

The only randomized trial (GOG protocol #20) of adjuvant chemotherapy in uterine sarcomas to date assigned patients to either doxorubicin, 60 mg/m2 every 3 weeks for eight cycles, or no further therapy (Table 117.4).85 For the overall patient population there were no significant differences in recurrence rate, progression-free interval, or survival between those who received no further treatment and those who received adjuvant doxorubicin. Although each of the two major histologic subsets contained too few patients for proper analysis, in each subset, a 12% or greater difference in recurrence rate was noted, favoring the group receiving doxorubicin. Overall median survival was 73.7 months for patients given doxorubicin and 55.0 months for those given no further therapy. The major deficiency in this study—its failure to take into account the difference in response of the two major histologic subsets—is the result of a lack of understanding of this distinction when the trial was conducted.

Table 117.4. Randomized Trials of Doxorubicin versus No Further Therapy in Completely Resected Stages I and II Uterine Sarcoma.

Table 117.4

Randomized Trials of Doxorubicin versus No Further Therapy in Completely Resected Stages I and II Uterine Sarcoma.

In September 1993, the GOG completed a study of adjuvant ifosfamide, mesna, and cisplatin in patients with completely resected stage I or II MMMT of the uterus.86 Ifosfamide was given in a dose of 1.5 g/m2 and cisplatin 20 mg/m2 daily for 5 days every 3 weeks for three cycles, with mesna uroprotection. Early in the study, the regimen was reduced to 4 days because of myelotoxicity. With a minimum of 2 years’ follow-up, 41 patients (63.1%) are progression-free and 48 (73.8%) are alive. These figures can be compared with those obtained in the GOG protocol #20 in which 54.5% of patients were progression free and 59.1% alive after adjuvant doxorubicin therapy, and 50% progression free and 62% alive after surgery alone.

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