Safety and efficacy of adjuvant single-agent ifosfamide in uterine sarcoma.

Kushner DM, Webster KD, Belinson JL, Rybicki LA, Kennedy AW, Markman M

Department of Gynecology and Obstetrics, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland Ohio 44195, USA

Between 1992 and 1999, 13 consecutive patients with completely resected moderate- to high-grade uterine sarcoma received three cycles of adjuvant ifosfamide (1.5 g/m(2)/day x 3 days, repeated every 28 days). Mesna was given 30 min prior to infusion. Postinfusion mesna was administered to 10 of the patients in the outpatient setting utilizing a subcutaneous infusion pump. The remaining 3 patients received traditional intravenous mesna at 4 and 8 h after infusion. RESULTS: The median follow-up of the patient population was 26 months. For early-stage patients (n = 10), the 2-year progression-free survival was 60%, with a median of 26 months. The 2-year overall survival was 100%, dropping to 67% at 3 years. Early-stage patients showed an advantage in both progression-free and overall survival. Early-stage patients with mixed mullerian tumor (MMT) had a significantly longer time to progression that those with leiomyosarcoma (LMS) (2-year progression-free survival of 100% versus 33%; P = 0.019). Three patients required dose reduction secondary to grade 2-3 toxicities (neutropenia x2, nausea and vomiting x1). All significant toxicity was eliminated with dose reduction. CONCLUSIONS: Adjuvant ifosfamide appears to be safe and well tolerated in patients with completely resected uterine sarcoma. It can easily be given in the outpatient setting if mesna is administered via a subcutaneous pump. Our data, consistent with previous studies in advanced sarcoma, suggest a potentially greater role for ifosfamide in MMT than in LMS.

Gynecol Oncol 1999 Sep;74(3):346-9

Phase II trial of paclitaxel in leiomyosarcoma of the uterus: a gynecologic oncology group study.

Sutton G, Blessing JA, Ball H

Division of Gynecologic Oncology, Indiana University Medical School, Indianapolis, Indiana, 46202, USA.

OBJECTIVE: The aim of this study was to determine the activity of paclitaxel in chemotherapy-naive patients with advanced or recurrent uterine leiomyosarcoma. METHODS: Patients received 175 mg/m(2) of paclitaxel iv over 3 h. Courses were repeated every 3 weeks until disease progression or adverse side effects supervened. RESULTS: Thirty-four women were entered, but 1 patient was ineligible because of wrong cell type. Median age was 55 years (range: 35-84 years). GOG performance status was 2 in 2 instances, 1 in 9 cases, and 0 in 22 others. Eight patients (23.4%) had received radiotherapy. A median of 2.5 courses was given (range: 1-18). Eleven patients (33.3%) experienced grade 3 or 4 neutropenia, 1 (2.9%) had grade 4 thrombocytopenia, and 1 had grade 3 anemia. There were no cases of grade 3 or 4 gastrointestinal or dermatologic toxicity. One patient each developed deep venous thrombosis and a grade 3 allergic reaction. Eight patients (24.2%) had stable disease for at least 2 courses of therapy. Three complete responses were reported (9.1%). CONCLUSION: With the dose and schedule tested, paclitaxel has limited activity in patients with uterine leiomyosarcoma. Modest toxicity suggests that a higher dose of paclitaxel might be evaluated.

Gynecol Oncol 1996 Aug;62(2):226-9

Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study.

Sutton G, Blessing JA, Malfetano JH

Section of Gynecologic Oncology, Indiana University Medical School, Indianapolis 46202, USA.

This is a Phase II groupwide study of the Gynecologic Oncology Group (GOG) to determine the toxicity and efficacy of a combination of ifosfamide and doxorubicin in patients with advanced or metastatic leiomyosarcomas of the uterus who had not received other chemotherapy. Thirty-five women were entered into this study; 1 patient was ineligible (primary not documented), leaving 34 patients treated with ifosfamide, 5.0 g/m2/24 hr, and mesna, 6.0 g/m2/36 hr, by continuous IV infusion preceded by doxorubicin, 50 mg/m2 iv over 15 min. Each course of therapy was repeated every 3 weeks if counts allowed. One patient was inevaluable for response, leaving 34 evaluable for toxicity and 33 evaluable for response of chemotherapy. GOG grade 3 or 4 granulocytopenia occurred in 17 patients (48.6%), 2 patients developed granulocytopenic fever (5.7%), and 1 died of sepsis. Two patients developed grade 3 thrombocytopenia, and 1 died of cardiotoxicity. There were nine partial and one complete responses for an overall response rate of 30.3%; the response duration averaged 4 months. The combination of ifosfamide and doxorubicin is toxic but has moderate activity in patients with advanced or metastatic leiomyosarcoma of the uterus.

Gynecol Oncol 1998 Aug;70(2):267-71

Prolonged oral etoposide in recurrent or advanced leiomyosarcoma of the uterus: a gynecologic oncology group study.

Rose PG, Blessing JA, Soper JT, Barter JF

Department of Obstetrics and Gynecology, Case Western Reserve University, Cleveland, Ohio, 44106, USA.

OBJECTIVE: In a previous study by the Gynecologic Oncology Group only modest activity was seen with bolus etoposide in leiomyosarcoma of the uterus (an 11% response rate). To exploit the schedule dependency of etoposide, which favors longer exposure, a Phase II trial of prolonged oral etoposide was conducted in this tumor. METHODS: Eligibility included leiomyosarcoma of the uterus, measurable disease, one prior chemotherapy regimen which did not include etoposide, WBC >/= 3000/microliter, platelet count >/=100, 000/microliter, serum creatinine </=2 mg%, and adequate hepatic function. The starting etoposide dose was 50 mg/m2/day (30-40 mg/m2/day for prior radiotherapy) as a single dose for 21 days, every 28 days. Based on toxicity, a dose escalation to a maximum etoposide dose of 60 mg/m2/day was prescribed. RESULTS: Thirty-six patients were entered on this study; 34 were evaluable for toxicity and 29 were evaluable for response. A median of 2 courses were given (range 1-14). Grade 4 neutropenia occurred in 20.6% and grade 4 thrombocytopenia occurred in 5.8%. One patient developed acute myeloid leukemia 10 months after completing 7 cycles of therapy. Among the patients evaluable for response, 27 had received prior chemotherapy and 6 had received prior radiation therapy. Two partial responses (6.9%) were observed. CONCLUSION: This regimen has minimal activity as second-line chemotherapy in leiomyosarcoma of the uterus. No benefit to the chronic oral schedule is evident.

Gynecol Oncol 1994 Apr;53(1):24-6

A phase II trial of ifosfamide and mesna in patients with advanced or recurrent mixed mesodermal tumors of the ovary previously treated with platinum-based chemotherapy: a Gynecologic Oncology Group study.

Sutton GP, Blessing JA, Homesley HD, Malfetano JH

Section of Gynecologic Oncology, Indiana University Medical School, Indianapolis 46202.

A phase II trial of ifosfamide and mesna in women with mixed mesodermal tumors of the ovary who had previously received platinum-containing chemotherapy was conducted by the Gynecologic Oncology Group (GOG). The starting dose of ifosfamide was 1.2 g/m2 daily iv for 5 days. Mesna was given intravenously with and at 4 and 8 hr following the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Thirty-two patients were placed on the study; 31 were evaluable for toxicity and 28 for response. Twenty-seven patients (87.1%) had previously undergone surgery and three (9.3%) had received radiotherapy before this trial. GOG grade 3 or 4 granulocytopenia occurred in 11 (35.5%) patients, and one (3.2%) developed grade 4 thrombocytopenia. Two patients (6.4%) had grade 3 neurotoxicity. A complete response was observed in one patient (3.6%) and partial responses in four patients (14.3%) for a total response rate of 17.9% (95% confidence interval = 6.1-36.9%). In conclusion, ifosfamide has activity in previously mixed mesodermal tumors of the ovary.

Am J Obstet Gynecol 1992 Feb;166(2):556-9

Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study.

Sutton GP, Blessing JA, Barrett RJ, McGehee R

Section of Gynecologic Oncology, Indiana University Medical School.

OBJECTIVE: The purpose of this study was to evaluate the activity of ifosfamide (isophosphamide) in patients with advanced or recurrent leiomyosarcoma not previously exposed to chemotherapy. STUDY DESIGN: This is a phase II groupwide study of the Gynecologic Oncology Group. Thirty-five patients were treated with ifosfamide 1.5 gm/m2 daily intravenously for 5 days with mesna (mercaptoethane sodium sulfonate). Fifty-six patients had received prior abdominal hysterectomy and 15 prior radiotherapy. The dose was reduced to 1.2 gm/m2 daily in patients who had received prior radiotherapy. RESULTS: Gynecologic Oncology Group grade III or IV granulocytopenia occurred in 4 (11%) patients, and none had grade IV thrombocytopenia. One (2.8%) patient had grade IV neurotoxicity. Partial responses were observed in 6 of 35 (17.2%) patients. The 95% confidence interval for response was 6.6% to 33.7%. CONCLUSION: These results indicate that ifosfamide has modest activity in patients with advanced or recurrent leiomyosarcomas of the uterus.

Anticancer Drugs 1996 Nov;7(8):885-9

Remission of advanced uterine leiomyosarcoma with pulmonary metastases with carboplatin and paclitaxel.

Kudelka AP, Termrungruanglert W, Vadhan-Raj S, Edwards CL, Varma DG, Tornos C, Verschraegen CF, Kavanagh JJ

University of Texas MD Anderson Cancer Center, Houston 77030, USA.

A patient who had a high-grade uterine leiomyosarcoma (LMS) with extensive intra-abdominal and pulmonary metastases at the time of diagnosis underwent supracervical hysterectomy, bilateral salpingo-oophorectomy and tumor reductive surgery. She then received induction chemotherapy with paclitaxel 135 mg/m2 over 24 h and carboplatin (target AUC = 7.5 mg.ml/min) monthly for seven courses, achieving remission with a small amount of residual disease. The treatment was well tolerated except for peripheral neuropathy. Accordingly, the combination of carboplatin and paclitaxel may be considered in patients with advanced high-grade LMS of the uterus, and this regimen warrants further study in this disease.

Gynecol Oncol 1995 Mar;56(3):370-5

A phase II study of etoposide, cisplatin, and doxorubicin chemotherapy in mixed mullerian tumors (MMT) of the uterus.

Resnik E, Chambers SK, Carcangiu ML, Kohorn EI, Schwartz PE, Chambers JT

Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Mixed Mullerian tumors (MMT) of the uterus are aggressive entities that result in a very poor prognosis even for patients in whom the disease is limited to the uterus. This phase II trial was undertaken in an attempt to improve overall survival as well as progression-free survival of these patients. Forty-two consecutive patients were treated with a combination chemotherapy containing etoposide 100 mg/m2 on Days 1 and 2, cisplatin 50 mg/m2 on Day 1, and doxorubicin 50 mg/m2 on Day 1, repeated every 28 days. There were 23 patients with early-stage disease (stages I and II) and 19 patients with advanced (stages III and IV) or recurrent disease. In the early-stage group, the number of cycles ranged from 2 to 9 (5.2 +/- 1.9). The median follow-up was 32 months (range 11-93). There were five recurrences: three patients died of disease at 11, 36, and 51 months, and two patients are still alive with disease at 12 and 19 months. Two-year overall survival was 92%. In the advanced disease group, the number of cycles ranged from 1 to 11 (5.9 +/- 2.4). The median follow-up for this group was 20 months (range 5-62). The median overall survival was 18 months. Two-year overall survival was 33%. Two-year progression-free survival was 20%. Four patients were evaluable for response. There were two complete responses (duration 15-33 months) and two partial responses (duration 6-10 months). The responders were patients whose adenocarcinoma component was of the papillary serous (UPSC) variety. The chemotherapy combination appears to be highly active in early-stage disease. In the advanced uterine MMT it has moderate activity, especially when associated with the UPSC component.

Am J Clin Oncol 1995 Aug;18(4):282-6

Impact on progression-free survival of adjuvant cyclophosphamide, vincristine, doxorubicin (adriamycin), and dacarbazine (CYVADIC) chemotherapy for stage I uterine sarcoma. A prospective trial.

Hempling RE, Piver MS, Baker TR

Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

To assess the impact on progression-free survival of the use of the multiagent chemotherapy regimen of cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dacarbazine (CYVADIC) as adjuvant treatment for patients with stage I uterine sarcoma: 20 evaluable patients who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage I uterine sarcoma received adjuvant multiagent chemotherapy with vincristine sulfate 1 mg/m2 days 1 and 4, doxorubicin (Adriamycin) 40 mg/m2 and cyclophosphamide 400 mg/m2 day 2, and dacarbazine 200 mg/m2 days 1 through 4 for a total of 9 monthly cycles or until recurrence of disease was documented. Patients were followed for a median of 65 months (range: 5-116 months). Myelotoxicity was monitored by weekly complete blood counts, cardiac toxicity by monthly radionuclide angiography, and neurotoxicity by monthly physical examination. Survival and progression-free survival were calculated by the method of Kaplan and Meier (17). The Fisher exact test was employed to determine the significance of recurrence rates between histologic groups (18). These 20 patients received 172 of a planned 180 cycles of chemotherapy. Dose reductions in response to myelotoxicity were necessitated in four cycles among three patients. Mild neurotoxicity was observed in six patients (30%) and moderate neurotoxicity in one patient (5%). A decrease in cardiac ejection fraction of > 10% was observed in two patients (10%). No deaths ascribable to complications arising from chemotherapy were observed. Seven patients (35%) developed recurrence of disease. Recurrence rates for pure sarcomas and mixed mesodermal tumors did not differ significantly (P = .65). Progression-free survival for the population at 2 years was 80% and at 5 years was 65%. This study describes the largest prospective trial of adjuvant combination chemotherapy for patients with stage I uterine sarcoma reported to date. Adjuvant chemotherapy employing the combination of cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dacarbazine (CYVADIC) failed to impact significantly on long-term survival in this group of patients with stage I uterine sarcoma.

J Clin Oncol 1987 Apr;5(4):618-21

Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.

Gershenson DM, Kavanagh JJ, Copeland LJ, Edwards CL, Stringer CA, Wharton JT

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.

Am J Clin Oncol 1991 Jun;14(3):246-50

Prospective trial of cisplatin, adriamycin, and dacarbazine in metastatic mixed mesodermal sarcomas of the uterus and ovary.

Baker TR, Piver MS, Caglar H, Piedmonte

Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263.

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.

Gynecol Oncol 1989 Sep;34(3):323-7

Cisplatin and adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors.

Peters WA 3d, Rivkin SE, Smith MR, Tesh DE

Puget Sound Oncology Consortium, Seattle, Washington 98104.

Twenty-eight patients with a uterine stromal sarcoma or mixed mesodermal tumor were treated with cisplatin 100 mg/m2 and Adriamycin 45-60 mg/m2, given with intravenous hydration every 3 to 4 weeks. Group I consists of 11 patients with measurable disease following initial surgery or with a recurrence. Eight of the eleven evaluable patients with measurable disease had a response (73%), and three of these patients have had a negative second-look procedure, and two are alive and disease free more than 24 months after initiation of treatment. Group II consists of 17 patients treated with adjuvant chemotherapy after primary surgery. The patients were selected for adjuvant therapy based on previous established poor prognostic features. Of the 17 patients in group II, 14 had invasion of the outer one-third of the myometrium and the other three had invasion to the middle one-third. Seven had documented positive pelvic and/or periaortic lymph nodes and five had positive peritoneal washings. With a median follow-up of 34 months, there have been only four recurrences in group II. Two of the recurrences occurred in patients who discontinued therapy after only two cycles of chemotherapy. There is a projected 5-year survival of 75% in these high-risk patients. Of the seven patients with documented nodal involvement, one patient died with a recurrence at 23 months, one patient died from a perforated diverticulum, and the other five are alive and disease free with a median follow-up of 36 months (34-90 months). Two patients with multiple positive nodes are disease free at more than 5 years. Combination chemotherapy with cisplatin and Adriamycin has a high response rate with advanced measurable disease and improves survival in high-risk patients who receive it as adjuvant therapy.

Cancer 1985 Apr 15;55(8):1648-53

Treatment of recurrent or advanced uterine sarcoma. A randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group).

Muss HB, Bundy B, DiSaia PJ, Homesley HD, Fowler WC Jr, Creasman W, Yordan E

Recurrent or metastatic uterine sarcoma represents an ominous and aggressive form of malignant disease. In an attempt to define a beneficial treatment program, we compared treatment with doxorubicin (A) 60 mg/m2 versus a combination of doxorubicin 60 mg/m2 and cyclophosphamide 500 mg/m (CA), each regimen given every 3 weeks. Of 132 patients entered on study, 104 were eligible; 50 received A and 54 CA. Pretreatment characteristics were similar, and no patient had received prior chemotherapy. The proportion of complete responses (CR) + partial responses (PR) for measurable disease patients was 5 of 26 (19%) for both A and CA. Multivariate analysis done on progression-free interval (PFI) and survival (S) showed CA to be of no benefit over A (PFI, P = 0.22; S, P = 0.55). For both A and CA patients, measurable disease (PFI, P = 0.002; S, P = 0.02, respectively), performance status (PFI, P = 0.004; S, P = 0.0002; respectively), and sites of residual disease (PFI, P = 0.008; S, P = 0.003, respectively) were detected as prognostic variables. Conversely, histologic type, age, and recurrence status (primary versus recurrent at entry) were not prognostic indicators. These data indicate no significant benefit of CA versus A alone in patients with uterine sarcoma.

J Surg Oncol 1988 Aug;38(4):233-9

Effect of adjuvant chemotherapy on time to recurrence and survival of stage I uterine sarcomas.

Piver MS, Lele SB, Marchetti DL, Emrich LJ

Department of Gynecologic Oncology, Roswell Park Memorial Institute, Buffalo, New York 14263.

We have evaluated the effect of adjuvant chemotherapy on time to recurrence and survival in two prospective trials of women with stage I uterine sarcomas. The first trial compared surgery only to surgery plus Adriamycin. The 5-year estimated survival rate was 36% for surgery alone and 63% for surgery plus Adriamycin. The 5-year recurrence free rate for surgery alone was 46% as compared to 75% for surgery plus Adriamycin. The second trial, without a concurrent control group, included patients with stage I uterine sarcoma and adjuvant cyclaphosphamide, vincristine, Adriamycin, and dacarbazine (CYVADIC) chemotherapy. The 5-year survival rate was 89% and the recurrence-free rate was 80%. In all of these trials, as well as in the report of Van Nagell et al (Cancer 57:1451-1454, 1986) of adjuvant vincristine, actinomycin-D, and cyclophosphamide (VAC) chemotherapy, there are too few patients to make any formal statistical comparison of the groups, although the surgery plus CYVADIC group appears to be the most promising.

Am J Clin Oncol 1998 Jun;21(3):306-7

A phase II trial of amonafide in patients with mixed mesodermal tumors of the uterus: a Gynecologic Oncology Group study.

Asbury R, Blessing JA, Podczaski E, Ball H

Department of Medicine in Oncology, University of Rochester School of Medicine, New York, USA.

Amonafide demonstrated a poor response rate and substantial toxicity in patients who had measurable, advanced mixed mesodermal tumors of the uterus.This dose schedule was associated with poor response rate and substantial toxicity.

Eur J Gynaecol Oncol 1990;11(4):307-12

The role of adjuvant chemotherapy in the treatment of uterine sarcoma patients.

Tore G, Topuz E, Bilce N, Aslay I, Dincer M, Elgin A

Department of Radiation Oncology, Istanbul University, Turkey.

41 uterine sarcoma patients completed their post-operative adjuvant treatment at Istanbul University, Oncology Institute. Of these patients 23 had pelvic irradiation (RT group) and 18 had pelvic irradiation plus chemotherapy (RT + CT group). The 3 year survival rates of the two adjuvant treatment arms were 36% (RT group) and 66% (RT + CT group) (0.05 greater than p greater than 0.02). This difference is statistically significant. The 5 year survival rates were 18% (RT group) and 51% (RT + CT group) (0.1 greater than p greater than 0.05). Although the survival advantage at 5 years is not statistically significant because of the low number of patients, the use of adjuvant chemotherapy in uterine sarcomas seems to bring some survival benefit, probably by controlling subclinical distant disease.