Mixed Mesodermal Sarcoma Research Articles

Uterine sarcoma - Accumulated 10 years experience

5175 Background: 40 patients with uterine sarcoma were treated at our service during the last 10 years. Their files were retrospectively reviewed and clinical data were collected and analyzed. Methods: The median age was 65 years (31–81). 39% had mixed mesodermal sarcoma, 29% had endometrial stromal sarcoma (16% high grade and 13% low grade), 27% had leyomiosacoma (17% high grade and 10% low grade) and 5% were classified as carcinosarcoma. 63% presented with stage I disease, 9% with stage II, 16% with stage III and 12% with metastatic disease. TAH+BSO was performed in 94% of patients. Adjuvant local radiotherapy was administered to 35% and adjuvant Adriamycin based chemotherapy to 12%. Results: Median follow up was 36 months. 11/28 (39%) of stage I-III patients radically operated recurred, 2 had local recurrence, 4 had local and distant failure and 5 had distant metastases only. The value of adjuvant post operative radiotherapy could not have been evaluated due to small number of patients in each subgroup. 5 year survival was 47% and it obviously correlated with disease stage (55% for stage I patients and 42% for stage II-IV) and histology and grade of the tumor (75% in low grade endometrial stromal and leyomiosarcoma, 60% in mixed mesodermal sarcoma, 50% in carcinosarcoma and 18% in high grade endometrial stromal and leyomiosarcoma). Conclusions: Our data are similar to other reported series as for prognostic factors and treatment results in this uncommon disease. No significant financial relationships to disclose.

Solid malignant uterine tumours

Uterine sarcomas are a rare group of uterine tumours. The majority consist of leiomyosarcomas, endometrial stromal and mixed mesodermal sarcomas. The most important treatment for this tumour group is removal of the uterus. Radiotherapy is of use in reducing the incidence of local relapse but its effect on the 5-year survival is not proven. Trials are currently evaluating chemotherapy for advanced or recurrent disease the most active agents being ifosfamide and doxirubicin.

A Phase III Trial of Ifosfamide with or without Cisplatin in Carcinosarcoma of the Uterus: A Gynecologic Oncology Group Study

Objective. The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide–cisplatin in this patient population.Methods. Patients were randomized to receive ifosfamide (1.5 g/m2/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m2/day) times 5 days. No patient had received previous chemotherapy.Results. Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin–ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide–cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for “other” metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test).Conclusion. The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.

Uterine Sarcomas: The Curie Institut Experience. Prognosis Factors and Adjuvant Treatments

Purpose.With a retrospective study at a single institution, we propose to analyze the prognosis factors and adjuvant treatment for uterine sarcomas.Materials and Methods.From 1975 to 1995, 73 uterine sarcomas were treated at the Institut Curie, corresponding to 61 T1, 5 T2, and 8 T4 tumors. Thirteen patients had metastatic disease at the time of diagnosis. The mean age was 58 years. In 71% of patients, the presenting sign was bleeding. This series consisted of 44% leiomyosarcomas (LMS), 19% endometrial stromal sarcomas (ESS), and 31% carcinosarcomas or mixed mesodermal sarcomas (MMS). For the grading classification, we used the classification of the Sarcoma Group of the French Federation of Cancer Centres for soft tissue sarcomas. Of the patients, 66% presented a high-grade tumor.Results.The median overall survival was 42 months, with a 5-year survival of 45%. Histological grade, FIGO stage, histology types, and menopausal status were the four independent factors in multivariate analysis. Eighteen patients relapsed locally (25.7%), with 77% central pelvic sites. Patients with radiotherapy and ESS had better local control in multivariate analysis. Thirty-four patients developed metastases (48.6%), mainly pulmonary (58.8%). Eight patients presented with peritoneal disease. High grades and LMS had the worst survival without metastasis in multivariate analysis.Conclusion.This study validated our classification for sarcoma grading and confirmed the finding of worst prognosis for LMS and the importance of radiotherapy in local control.

Uterine sarcoma in the south of Israel: study of 36 cases.

Uterine sarcomas are rare, charaterized by rapid clinical progression and poor prognosis, and their management has been a challenge. The purpose of this study was to investigate the clinical and histologic findings, treatment, and outcome of patients with uterine sarcoma in the south of Israel. Data from the files of 36 patients with uterine sarcoma who were managed at the Soroka Medical Center between January 1961 and December 1994 were evaluated. The 5-year survival rate was 32% overall; 63% for 9 patients with endometrial stromal sarcoma (ESS). 30% for 14 patients with mixed mesodermal sarcoma (MMS) and 18% for 13 patients with leiomyosarcoma (LMS): 41% for 22 patients with Stage I and 19% for 14 patients with Stages II, III, and IV. Only the difference in the 5-year survival rate between ESS and LMS was statistically significant (P < 0.05). Eleven patients (30.6%) were treated with surgery alone, 4 (11.1%) with surgery followed by pelvic radiotherapy, 11 (30.6%) with surgery followed by chemotherapy, 8 (22.2%) with surgery followed by pelvic radiotherapy and chemotherapy, one (2.8%) with chemotherapy alone, and one (2.8%) had no treatment. Uterine sarcomas are aggressive tumors with a poor prognosis. The treatment is surgery generally followed by adjuvant pelvic radiotherapy and/or systemic chemotherapy.

Mixed mesodermal sarcoma of the ovary in a young patient

Mixed mesodermal tumors (MMT) of the ovary are rare and have a poor prognosis. This ovarian malignancy usually occurs in postmenopausal women. We report an unusual ovarian MMT in a young woman given treatment similar to one used for ovarian germ cell malignancies. We believe this is the youngest patient reported with an homologous MMT of the ovary.

Radiotherapy in the treatment of uterine sarcomas. A retrospective analysis of 54 cases.

In the general population, uterine sarcoma (US) is an uncommon tumor, which accounts for approximately 1-3% of all uterine neoplasms. Its biological behavior is characterized by hematogenous metastases and local recurrent growth including the pelvis and peritoneal cavity. In the management of US, surgery is the primary form of treatment. Up to now the role of adjuvant radiotherapy has not been clearly established. We report about 54 patients with US treated from 1954 to 1994 by surgical resection alone (22) or a combination of surgery and irradiation (32) and evaluate the influence of histology, stage and different treatment options on survival. Our data indicate an increased disease-free survival for patients treated with adjuvant radiotherapy, especially if poor prognostic factors are present (advanced tumor stage, histopathological grade II or III of leiomyosarcoma and mixed mesodermal sarcoma). Postoperative irradiation using doses between 50 and 60 Gy is recommended, in selected cases brachytherapy should be added. Prospective multicentric trials including a statistically evaluable number of patients are necessary to further clarify the role of multimodality treatment programs for US.

DNA-content in endometrial carcinoma of tamoxifen-treated breast cancer patients.

DNA measurements and histopathologic evaluation were performed in 17 patients treated with adjuvant tamoxifen for early breast cancer and who developed endometrial carcinoma during or after the tamoxifen therapy. The tumors were exclusively characterized by euploid DNA content except for two cases, one mixed mesodermal sarcoma, a highly malignant and rare tumor, and one adenocarcinoma. Although the use of adjuvant tamoxifen therapy most likely enhances the risk of developing endometrial carcinoma, the beneficial effects of adjuvant breast cancer treatment is of well-known clinical importance. The hazards of giving long-term tamoxifen seem to be low since the endometrial tumors were associated with low-grade malignancy and euploid DNA pattern.

Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study.

Ninety-six assessable patients with advanced or recurrent uterine sarcomas, who were no longer controllable with surgery and radiotherapy, and who had not received prior chemotherapy were treated with cisplatin 50 mg/m2 intravenously every 3 weeks. Of 63 cases with mixed mesodermal tumors, five complete responses (CRs; 8%) and seven partial responses (PRs; 11%) were observed (95% confidence interval [CI], 10.3% to 30.9%). Of 33 patients with leiomyosarcoma, one PR (3%) was observed (95% CI, .1% to 15.8%). Adverse effects included leukopenia (23%), nausea and vomiting (73%), and mild azotemia (42%). No patients experienced life-threatening toxicity. Cisplatin has definite activity when given at the dose and schedule that we tested for patients with mixed mesodermal sarcomas who have not received prior chemotherapy, but has little activity in patients with leiomyosarcoma.

Prospective Trial of Cisplatin, Adriamycin, and Dacarbazine in Metastatic Mixed Mesodermal Sarcomas of the Uterus and Ovary

Twenty-four patients with advanced or recurrent uterine (13) and ovarian (11) mixed mesodermal sarcomas received a combination of cisplatin. Adriamycin and dacarbazine (PAD) as initial therapy after surgical debulking. Of the 13 patients with metastatic uterine sarcoma, six (46.1%) remained without evidence of disease (NED) from 8 to 36 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 68%, 68%, and 51%, respectively. Of the 11 ovarian sarcoma patients, five (45.4%) were NED at 5, 7, 32, 56, and 59 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 70%, 35%, and 35%, respectively. The PAD regimen is an active regimen in patients with metastatic uterine and ovarian mixed mesodermal sarcomas and progression-free survival may be improved by maximum debulking surgery prior to the initiation of PAD chemotherapy.

A phase II trial of diaziquone (AZQ) in mixed mesodermal sarcomas of the uterus

AZQ was given intravenously to 23 patients with mixed mesodermal sarcoma of the uterus refractory to conventional treatment at a dose of 22.5-30 mg/m2 q three weeks. There was one partial response lasting seven weeks and one drug-related death. Based upon the activity observed in this trial, there does not appear to be a significant role for AZQ as a salvage agent for mixed mesodermal sarcomas of the uterus at the dose and schedule tested.

Patterns of metastasis in uterine sarcoma, an autopsy study

The autopsy findings of 73 patients with uterine sarcoma were studied to determine the sites and possible modes of metastasis. Homologous mixed mesodermal tumors were the most frequent (41%) followed by leiomyosarcoma (26%), heterologous mixed mesodermal tumor (18.3%), stromal sarcoma (12%), and endolymphatic stromal myosis (3%). The peritoneal cavity and omentum were the most frequently involved sites (59%), followed by the lung (52%), pelvic lymph nodes (41%), paraaortic lymph nodes (38%), and liver parenchyma (34%). The presence of lung metastasis was not associated with pelvic or paraaortic node metastasis or intraperitoneal disease. Metastasis to other distant sites including the brain, heart, kidney, and bone were independent of pelvic and paraaortic nodal metastasis or intraperitoneal disease. Metastatic sites were not different among various histologic types. Distant metastatic sites were statistically associated with lung metastasis. Hematogenous metastasis best explains this metastatic pattern and adjuvant systemic therapy seems indicated.

Immunoperoxidase labelling of rat brain sections with sera from patients with paraneoplastic cerebellar degeneration and systemic neoplasia.

Sera from patients with systemic cancer found by immunofluorescence staining to have antibodies to human cerebellar cell populations were reacted with vibratome sections of rat cerebellum and examined by peroxidase-antiperoxidase (PAP) methods. Seven patients with clinically or pathologically confirmed paraneoplastic cerebellar degeneration and two neurologically normal patients with high titers of anticerebellar antibodies were studied. Sera from all antibody-positive patients, but not from controls, produced intense staining of brain sections. Sera from patients with ovarian adenocarcinoma reacted predominantly with Purkinje cells and neurons within brainstem nuclei. Sera from patients with oat cell carcinoma and one patient with ductal carcinoma of the breast produced nuclear and cytoplasmic staining of neurons throughout the central nervous system. Serum from a patient with Hodgkin's disease labeled the peripheries of Purkinje cells and Golgi II cells. Serum from a patient with mixed mesodermal sarcoma of the ovary labeled Purkinje cells, basket cells, and scattered astrocytes. Staining of extraneural tissues was not observed. This study confirms the presence of antineural antibodies in patients with systemic neoplasia with and without paraneoplastic cerebellar degeneration and suggests that the antigens recognized by this antibody response may vary with the associated neoplasm.

In vitro growth characteristics and chemosensitivities of endometrial cancer using a soft agar clonogenic assay

A soft agar clonogenic assay was used to analyze 91 fresh human endometrial tumor samples for in vitro growth and chemosensitivities. Overall cloning success was 81%. Of the 75 samples adequate for drug testing (30 or more colonies per plate), histologic analysis demonstrated 36 adenocarcinomas, seven adenoacanthomas, ten adenosquamous carcinomas, nine mixed mesodermal sarcomas, seven carcinosarcomas, three papillary adenocarcinomas, and three clear-cell carcinomas. Mixed mesodermal sarcoma specimens demonstrated the most efficient growth, followed by the adenosquamous adenocarcinoma and adenoacanthoma samples. In vitro chemosensitivities were determined by colony inhibition resulting from continuous exposure of tumor cells to known achievable peak plasma and one-tenth peak plasma concentrations of a particular agent. The plating efficiency reflected the clinical virulence by cell type. Thus, we found that malignant endometrial tumors can be cloned in vitro, and the observed chemosensitivities reflect the relative clinical resistance of the tumors to these agents. Based on the high cloning success, this tumor type may be well suited as a model using in vitro soft agar cloning for new drug screening, evaluation of novel drug combinations, and studies of human tumor biology.

Chemotherapy for advanced or recurrent gynecologic cancer.

Studies of chemotherapy in advanced or recurrent gynecologic cancer have focussed on ovarian, cervical, and endometrial carcinoma. For celomic epithelial carcinomas of the ovary, a large number of cytotoxic agents have been shown to be active. Dramatic improvement in frequency of response with lesser improvement in survival has been noted with the use of cisplatin-based combination chemotherapy as compared to single alkylating agents. More recent studies have evaluated alternative ways to employ cisplatin: higher dose schedules, intraperitoneal administration, and platinum compounds with a potentially better therapeutic index. None has yet been shown superior to a combination of relatively low-dose cisplatin plus an alkylating agent with or without doxorubicin. Cisplatin remains the best studied and most active single agent in patients with squamous cell carcinoma of the cervix. While a number of other agents have demonstrated moderate activity, no combination of drugs has as yet proved superior to single-agent cisplatin. In endometrial carcinoma, progestins and doxorubicin are the most active agents. Tamoxifen, cisplatin, and hexamethylmelamine appear to have moderate activity. No combination has yet been shown to be superior to single agents. Information on chemotherapy for less common gynecologic malignancies is largely anecdotal. Two observations are of note. Cisplatin-based combination chemotherapy is highly active against germ-cell neoplasms of the ovary. Cisplatin also has definite activity against mixed mesodermal sarcoma of the uterus.

Cyclophosphamide, hexamethylmelamine, adriamycin and cisplatin combination chemotherapy in mixed mesodermal sarcoma of the female genital tract

Clinically mixed mesodermal sarcoma is a different entity among the other subtypes of soft tissue sarcomas. Although adriamycin is considered to be the most active single agent in the treatment of adult soft tissue sarcomas, the drug has only limited activity in mixed mesodermal sarcomas. On the other hand, cisplatin is inactive in soft tissue sarcomas, but was reported to be active in mixed mesodermal sarcomas. Therefore combinations including both adriamycin and cisplatin appear attractive for testing in the treatment of mixed mesodermal sarcomas. We have performed a pilot study with two combinations in mixed mesodermal sarcomas of the female genital tract. Two patients treated with adriamycin and cisplatin showed rapid progression. Of 7 patients treated with cyclophosphamide, hexamethylmelamine, adriamycin and cisplatin (CHAP-5), 6 had measurable disease, of whom 5 yielded a response (2 complete responses for 19+ and 40 months and 3 partial responses for 4, 7 and 8 months). The patient with non-measurable disease had a progression-free survival of 27 months. The median survival for all CHAP-5-treated patients was 20 months. This regimen is recommended for further phase II studies.

High-dose doxorubicin infusion therapy for disseminated mixed mesodermal sarcoma of the uterus.

Fifteen patients with metastatic mixed mesodermal sarcoma of the uterus received high dose doxorubicin infusion therapy. For 12 patients, the initial dose was 90 mg/m2; the other three patients' starting doses were 50, 75, and 75 mg/m2 respectively. Twelve patients received doxorubicin as firstline chemotherapy, with a cumulative dose of 90 mg/m2 to 675 mg/m2 (median = 495 mg/m2). Three patients treated secondarily received cumulative doses of 90, 205, and 425 mg/m2. Of nine patients who had measurable disease, none had an objective response. The median survival of the 15 patients was 11.3 months, with a range of 0.5 to 51+ months. Two patients died of neutropenia related sepsis. Cardiotoxicity occurred in two patients. Eleven patients are dead of disease, and two patients are alive without evidence of disease at 49, and 51 months. Extending the doxorubicin dosage to its tolerable limits did not appear to result in improved efficacy in patients with metastatic mixed mesodermal uterine sarcomas. Future clinical trials should concentrate on doxorubicin-containing combination regimens and Phase II single agent studies.

Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.

Cyclophosphamide versus ifosfamide: Final report of a randomized phase II trial in adult soft tissue sarcomas

Ifosfamide (IFOS) 5 g/m 2 and its parent analog Cyclophosphamide (CYCLO) 1.5 g/m 2 were studied in a randomized phase II study, accruing 171 patients with advanced soft tissue sarcoma. Both drugs were administered as 24 hr infusions, every 3 weeks, with comcomitant Mesna 400 mg/m 2 i.v. bolus 4 hourly × 9 doses. Twenty-four patients were ineligible and 12 were not evaluable. The groups were well matched for age, previous chemotherapy ( 42% of the total) or radiotherapy, the presence of distant metastases and performance status, but there were more females ( 59% vs. 45%) in the IFOS arm. Among the 68 evaluable patients receiving IFOS, there were 2 CR, 10 PR (overall response 18%), 27 SD and 29 PD. For CYCLO, the corresponding results in 67 patients were 1 CR, 4 PR (overall response 8%), 23 SD and 39 PD. Using the chi-square test the P values for response rate and linear trend were 0.13 and 0.04 respectively. Response rates were higher for females ( 20% vs. 5%, P = 0.01) and patients who had not received previous chemotherapy ( 19% vs. 4%, P = 0.01). Fourteen of the 17 responses came from a group of 43 females, who had not received previous chemotherapy, for whom the overall response rate was 37.5%. Remissions were noted in only 4 histological subtypes (centrally reviewed material), i.e., 5 of 17 synovial sarcomas, 7 of 13 mixed mesodermal sarcomas and 2 of 7 fibrosarcomas. One of the 31 leiomysarcomas responded to Cyclophosphamide. Durations of response did not differ significantly between the 2 arms—median 26, range 10–81 + weeks. Leucopenia was significantly more severe on CYCLO, particularly in patients who had received previous chemotherapy ( P = 0.007). Serious infections occurred in approx. 7% of patients with no difference between the two drugs, although there was one toxic death on CYCLO. Nausea and vomiting were significantly worse on IFOS and alopecia, related in extent to dose, was seen in both arms. Other side-effects, such as hematuria or rises in serum creatinine and encephalopathy, were infrequent and mild. A higher response rate with less myelosuppression suggests that IFOS may have advantages over CYCLO in combination therapy.

The Epidemiology of Sarcomas of the Uterus

Data from nine population-based cancer registries (1973-81) were analyzed to examine the demographic characteristics that are related to the occurrence of sarcomas of the uterus. Leiomyosarcoma and mixed mesodermal sarcoma accounted for 86% of 1,452 uterine sarcomas reported, and both were more common in black women than in white women. The incidence of mixed mesodermal sarcoma was low through middle age, after which it rose sharply. The incidence of uterine leiomyosarcoma, however, was highest in middle-aged women and declined thereafter. The age-incidence pattern of uterine leiomyosarcoma resembles that of carcinomas of the female reproductive tract, unlike the pattern of other uterine sarcomas or sarcomas occurring elsewhere. This suggests that one or more factors that play a role in the etiology of carcinomas of the reproductive tract may be involved in the etiology of this tumor as well.