GYNECOLOGIC ONCOLOGY 62, 226–229 (1996)ARTICLE NO. 0220

Ifosfamide and Doxorubicin in the Treatment of AdvancedLeiomyosarcomas of the Uterus: A Gynecologic

Oncology Group Study1

GREGORY SUTTON, M.D.,* JOHN A. BLESSING, PH.D† AND JOHN H. MALFETANO, M.D.‡

*Section of Gynecologic Oncology, Indiana University Medical School, Indianapolis, Indiana 46202; †Gynecologic Oncology Group,Roswell Park Cancer Institute, Buffalo, New York 14263; and ‡Department of Obstetrics and Gynecology,

Albany Medical Center Hospital, Albany, New York 12208

Received September 22, 1995

Because previous studies by the GOG demonstrated thatThis is a Phase II groupwide study of the Gynecologic Oncology doxorubicin could produce responses in up to 25% of such

Group (GOG) to determine the toxicity and efficacy of a combina- patients [3], it seemed logical to combine ifosfamide andtion of ifosfamide and doxorubicin in patients with advanced or doxorubicin in a phase II study of patients with advancedmetastatic leiomyosarcomas of the uterus who had not received or recurrent leiomyosarcoma who had received no previousother chemotherapy. Thirty-five women were entered into this chemotherapy.study; 1 patient was ineligible (primary not documented), leaving34 patients treated with ifosfamide, 5.0 g/m2/24 hr, and mesna,

MATERIALS AND METHODS6.0 g/m2/36 hr, by continuous IV infusion preceded by doxorubicin,50 mg/m2 iv over 15 min. Each course of therapy was repeated

Patients with histologically proven advanced or recurrentevery 3 weeks if counts allowed. One patient was inevaluable forleiomyosarcoma of the uterus not amenable to curative ther-response, leaving 34 evaluable for toxicity and 33 evaluable forapy but unexposed to prior chemotherapeutic agents wereresponse of chemotherapy. GOG grade 3 or 4 granulocytopeniaeligible for this study. Additional eligibility criteria includedoccurred in 17 patients (48.6%), 2 patients developed granulocyto-the presence of measurable disease that could be defined inpenic fever (5.7%), and 1 died of sepsis. Two patients developed

grade 3 thrombocytopenia, and 1 died of cardiotoxicity. There at least two dimensions by physical examination or medicalwere nine partial and one complete responses for an overall re- imaging techniques. Ascites and pleural effusions were notsponse rate of 30.3%; the response duration averaged 4 months. considered measurable. Also required were GOG perfor-The combination of ifosfamide and doxorubicin is toxic but has mance status of 2 or better [4], an interval of 3 weeks or moremoderate activity in patients with advanced or metastatic leiomyo- since any prior tumor-directed therapy, absence of significantsarcoma of the uterus. q 1996 Academic Press, Inc. infection, recovery from recent surgery or radiotherapy, and

adequate white blood cell count (§3000/ml), platelet count(§100,000/ml), and hepatic (serum bilirubin, alanine trans-INTRODUCTIONferase, and alkaline phosphatase£ 2 times normal) and renal

Women with stage I or II leiomyosarcomas of the uterus (serum creatinine £ 1.5 mg/dl or creatinine clearance §may be cured with hysterectomy 40–50% of the time [1]. 50 ml/min) function tests. Written informed consent wasExcept for the rare patient with a resectable isolated pulmo- obtained from all patients prior to entry on study, fulfillingnary metastasis, those who suffer recurrences following ther- all institutional, state, and federal regulations.apy or present with metastatic disease have a poor prognosis. Criteria for exclusion were absence of measurable disease,In 1986, the Gynecologic Oncology Group (GOG) initiated prior chemotherapy, GOG performance status of §3, pres-a series of phase II studies of promising new drugs in women ence of a second malignancy excluding squamous or basalwith advanced or metastatic leiomyosarcoma of the uterus skin lesions, or the presence of microhematuria in excess ofwho had received no previous chemotherapeutic treatment. the institutional lowest normal range. Additional exclusionAmong the drugs evaluated as part of that study, ifosfamide criteria included history of myocardial infarction within the[2] had definite activity, yielding a response rate of 17.2%. preceding 6 months, history of congestive heart failure, or

past mediastinal irradiation. Patients with uncorrected hydro-nephrosis were also ineligible for this study since hydrone-1 Reprint requests should be addressed to GOG Administrative Office,

Suite 1945, 1234 Market Street, Philadelphia, PA 19107. phrosis predisposes to ifosfamide toxicity.

2260090-8258/96 $18.00Copyright q 1996 by Academic Press, Inc.All rights of reproduction in any form reserved.

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227IFOSFAMIDE, DOXORUBICIN, AND MESNA IN LEIOMYOSARCOMAS

TABLE 1Ifosfamide was administered intravenously at a dose of 5Patient Characteristics and Responseg/m2/24 hr by continuous infusion admixed with mesna, 6

to Doxorubicin and Ifosfamideg/m2/36 hr, by continuous infusion. Doxorubicin was givenin a dose of 50 mg/m2 over 15 min iv preceding the ifosfam-

Responseide and mesna. The maximum total dose of doxorubicin was450 mg/m2. Chemotherapy was given every 3 weeks if Characteristic Complete Partial Totalcounts permitted and doses were reduced by 20% if the

Number 33patient had received radiotherapy to the pelvis or abdomenAge (years) 39 55 55before enrolling in the study. History and physical examina-

Median 42–67 30–70tion with assessment of evaluable lesions, GOG performanceGOG performance status

status, serum chemistry results, blood urea nitrogen, creati- 0 1 6 13nine, and microscopic urinalysis were performed before each 1 0 3 16

2 0 0 4cycle of therapy, and complete blood cell count and differen-Prior radiotherapytial and platelet counts were obtained weekly. A chest radio-

Yes 0 2 9graph was required on entrance to study and every 3 weeksNo 1 7 24

if a marker lesion was present. Abdominal and pelvic com- Prior hysterectomyputed tomographic scans were used to measure response Yes 1 7 29

No 0 2 4unless tumor parameters were assessed by examination orchest radiograph.

Drug administration was delayed after hematologic toxic-ity until white blood cell count wasú3000/ml, platelet count m2 initially. The remainder received a reduced dose becauseú100,000/ml, and granulocyte count ú1500/ml. Patients of previous radiotherapy. Seventeen patients (48.6%) experi-were considered evaluable for toxicity if just one course of enced GOG grade 3 or 4 granulocytopenia (granulocytetherapy was given and evaluable for response after a single count õ 1000/ml), and there were two instances of relatedcourse of therapy if there was clear-cut progression. In other fever and one died of sepsis. The median nadir for whitecases, patients remained on study until disease progression blood count was 1150/ml with a range of 500–2900/ml inwas noted or adverse effects or declining performance status patients experiencing leukopenia. A single death was attrib-prevented further therapy. Response duration was calculated uted to cardiac toxicity. This occurred in a 69-year-old whitefrom the start of therapy until documentation of disease pro- female with a history of hypertension and diffuse pulmonarygression. Patients were considered to have stable disease if metastases. She developed dyspnea after receiving a totalthere was no progression of disease during therapy for 4 dose of 70.6 g of ifosfamide and 748 mg of doxorubicin (36.6months. g/m2 and 383 mg/m2, respectively). She died of refractory

congestive heart failure. There was one instance of ifosfam-ide-related grade 2 renal toxicity and no cases of ifosfamide-RESULTSrelated neurotoxicity were reported by participating institu-tions.Between May 1991 and August 1992, 35 patients were

entered into this study. One patient was found to be ineligibleby the GOG Pathology Committee because of inability to Responsedocument the histologic nature of the primary tumor. One

Table 1 outlines patient characteristics and the clinicalpatient was inevaluable for response, leaving 34 evaluableresults of therapy with ifosfamide and doxorubicin. Ninefor toxicity and 33 evaluable for response to chemotherapy;patients (27.3%) experienced a partial response to therapy1 patient did not receive a full course of therapy. The medianand one had a complete response (3.0%) for an overall re-age of patients in this study was 55, with a range of 30sponse rate of 30.3%. Seventeen subjects (51.7%) had stableto 70 years. Twenty-nine patients had undergone previousdisease. Median response duration was 4.1 months (range,hysterectomy, 1 had laparotomy only, 1 had a biopsy only,1.0 to 26.0 months) in partial responders and response dura-and 2 had no surgery. Nine patients (27.3%) had receivedtion was 8.7 months in the patient with the complete re-prior pelvic or abdominopelvic radiotherapy. Thirteen pa-sponse. Response by GOG performance status is shown intients had GOG performance status 0, 16 had GOG perfor-Table 1. Median age for partial responders was 55 years asmance status 1, and 4 had GOG performance status 2.was the median age for the entire study; the complete re-sponder was 39 years of age. Two partial responders hadToxicityreceived radiotherapy before chemotherapy and partial re-sponders received a median of 8 cycles of chemotherapyTwenty-four patients had ifosfamide administered at a

dose of 5 g/m2/24 hr and doxorubicin at a dose of 50 mg/ (range, 3–11 cycles), with a median of 5 cycles until the

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228 SUTTON, BLESSING, AND MALFETANO

response was documented. Median survival for responders In the present study, there was a response rate of 30.3%(95% confidence interval of 15.6 to 48.7%) in untreatedwas 11.1 months and 9.6 for the group as a whole.patients, albeit with a response duration of only 4 months.Toxicity was of concern, especially the case of congestiveDISCUSSIONheart failure. In combination chemotherapy, doxorubicin-related congestive heart failure is rarely observed when dosesThe treatment of uterine sarcomas continues to be a chal-

lenge. Although adjuvant radiotherapy may reduce the risk are held below 450 mg/m2 [2, 16]. Although three cases ofventricular premature contractions in association with ifos-of local recurrence in patients with early stage mixed mulle-

rian tumors, such treatment has not been advantageous in famide therapy were reported by Takahashi et al. [17], otherextensive reviews [18, 19] indicate that ifosfamide is remark-women with early leiomyosarcomas because pulmonary me-

tastases are more common than pelvic recurrences [1]. Up ably free of adverse cardiac effects. Whether ifosfamide po-tentiated the cardiac effects of doxorubicin in the patientto 50% of women with stage I or II disease at presentation

develop recurrences following initial therapy and many pa- described above remains uncertain. In their extensive experi-ence with doxorubicin, ifosfamide, and dacarbazine in softtients present with stage III or IV disease. In a few women,

metastectomy may be beneficial [5]. Chemotherapy remains tissue sarcoma, Elias et al. [20] reported no cardiotoxicity.Ifosfamide and doxorubicin doses were 7.5 g and 60 mg/experimental. Hormonal treatment of gynecologic sarcomas,

with the exception of steroid-responsive endometrial stromal m2, respectively, in their study of 108 patients.Although the combination of ifosfamide and doxorubicinsarcomas [6], is usually futile [7].

In the past, few chemotherapeutic trials distinguished be- is moderately active, it is unclear whether this regimen hasan advantage over doxorubicin alone. Other more activetween leiomyosarcomas and mixed mullerian tumors of the

uterus. Omura et al. [3] compared doxorubicin alone or in agents need to be developed before meaningful treatment isavailable to patients with these neoplasms.combination with dacarbazine in uterine sarcomas. Twenty-

five percent of patients with leiomyosarcomas responded totreatment whereas responses were observed in only 9.8% ACKNOWLEDGMENTSof those bearing mixed mullerian tumors. Similarly, whendacarbazine was added, the response rates for patients with This study was supported by National Cancer Institute grants of the

Gynecologic Oncology Group Administrative Office (CA 27469) and thethe two tumors were 30 and 22.6%, respectively. In laterGynecologic Oncology Group Statistical Office (CA 37517). The followingGOG studies [8, 9] cisplatin administration was associatedGynecologic Oncology Group institutions participated in this study: Univer-with a response rate of 18% of patients with doxorubicin– sity of Alabama at Birmingham, Oregon Health Sciences Center, Duke

refractory mixed mullerian tumors and only 5.3% of patients University Medical Center, Wayne State University School of Medicine,with similarly treated leiomyosarcomas. Of 33 chemother- Colorado Foundation for Medical Care, University of Miami School of

Medicine, The Milton S. Hershey School of Medicine of the Pennsylvaniaapy-naive patients with recurrent or metastatic leiomyosar-State University, Georgetown University Hospital, University of Cincinnaticoma, only one partial response (3%) was observed withCollege of Medicine, University of North Carolina School of Medicine,cisplatin administration in a later Gynecologic Oncology Indiana University Medical Center, Bowman Gray School of Medicine of

Group study [10]. The differential sensitivity to chemother- Wake Forest University, State University of New York at Syracuse, Theapy in the two types of sarcomas resulted in segregation of Albany Medical College of Union University, Tufts New England Medical

Center, The Johns Hopkins Oncology Center, State University of New Yorkleiomyosarcomas from mixed mullerian tumors in subse-at Stony Brook, Washington University School of Medicine, Memorialquent Gynecologic Oncology Group studies.Sloan–Kettering Cancer Center, Columbus Cancer Council, University ofIfosfamide was a very active drug in women with ad- Texas, M. D. Anderson Cancer Center, Medical University of South Caro-

vanced or metastatic mixed mullerian tumors of the uterus lina, and University of Oklahoma Health Science Center.in a Gynecologic Oncology Group phase II trial [11], produc-ing a response rate of 32.2% in untreated patients. Although REFERENCESnot as active in leiomyosarcomas (response rate, 17.2%) [2],ifosfamide compares very favorably with other drugs studied 1. Major, F. J., Blessing, J. A., Silverberg, S. G., Morrow, C. P., Creasman,in well-controlled phase II trials by the Gynecologic Oncol- W. T., Currie, J. L., Yordan, E., and Brady, M. F. Prognostic factors

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