Adjuvant therapy in mixed mullerian tumors of the uterus

GYNECOLOGIC

ONCOLOGY

23,

212-221 (1986)

Adjuvant Therapy In Mixed Mullenan Tumors of the Uterus ERNEST I KOHORN,’ PETER E SCHWARTZ, JOSEPH T CHAMBERS; RICHARD E PESCHEL, DANIEL S KAPP, AND MARIA MERINO Departments of Obstetrics and Gynecology, Therapeutic Radiology, and Pathology, Yale Unrverslty School of Medmne, New Haven, Connecticut 06510 Received February 20, 1985

We report 54 patients with mixed mullenan tumors of the uterus treated at Yale-New Haven Hospital from 1962 to 1983 Seven had previous pelvic lrradlatlon Twenty-five neoplasms were homologous and 29 were heterologous The mainstay of therapy was surgery and radiation By FIG0 cntena 9 patients had stage IA disease, 31 stage IB, 6 stage II, and 8 patients had clinical extrauterme disease Ten of forty-six patients (23%) with FIG0 stage I and II disease had extrauterme disease found at surgery No patient with extrauterme disease had prolonged survival The 2-year disease-free survival with stage IA was 66%, with stage IB suracally confirmed 32%, and for stage II 33% Surgically advanced disease m clinical stage I and II patients and recurrence were associated more frequently with a heterologous histology (67%) The small uterus with a less than IO-cm cavity had a better prognosis Among 29 surgically confirmed stage I and II patients, 83% of recurrences appeared wlthm 2 years (mean 16 months 2 7 months) Patients who received both mtracavltary radiation and external beam developed only 17 6% pelvic recurrence but this reduction m local recurrence was not associated with significant improved long-term survival Six of eight patients treated with cls-platinum, Adnamycm, and dlmethyl tnazeno lmldazole carboxlmlde for persistent disease or for recurrence showed response for 4 to 24 months, none complete Five patients were treated by radiation, surgery, and adjuvant chemotherapy (4 with Adnamycm-Cytoxan, 1 with Adnamycm-platinum) Four of the five (80%) are disease free from 36 to 60 months These data and the experience of others support the need for a clinical tnal with adjuvant platinum and Adnamycm m this disease D 1986 Academic Press Inc

INTRODUCTION The contmumg reports concerning mixed mullerlan tumors of the uterus attest to the active pathologc mterest and the chmcal frustration associated with managmg patients with these neoplasms Most recent studies have concentrated more on the clinical correlates than on the vaganes of the hlstologlc classlficatlon The controversies whether primary surgical staging 1s mandatory or whether pelvic u-radlatlon should precede surgical exploration continues The role of presently available chemotherapy as an adJuvant with primary treatment remains controversial, and therapy for metastatlc disease contmues to be frustrated by msufkently ’ To whom repnnt requests should be addressed Medlcme, 333 Cedar St , New Haven, Conn 06510 212 0090-8258/86 $1 50 Copynghl All n&s

Q 1986 by Academic Press Inc of reproduction m any form reserved

Dept Ob/Gyn, Yale Umverslty School of

MIXED

MULLERIAN

TUMORS

RADIATION/CHEMOTHERAPY

213

effective drugs The experience with mixed mullerlan tumors at Yale-New Haven Medical Center 1s presented to reiterate the problems previously encountered, to recount the experience with adjuvant radiation and chemotherapy during pnmary treatment, and to document that combmatlon chemotherapy may be of benefit for patients with recurrent disease MATERIALS

AND METHODS

Patient records of the Departments of Gynecology, Pathology, and Therapeutic Radiology at Yale University School of Medicine were reviewed Fifty-four patients with hlstologlcally documented mlxed mullerlan tumors of the uterus were seen at Yale-New Haven Medical Center m the 20-year penod 1963 to 1983 Their mean age was 66 years, median 67 years, with a range of 40 to 88 years Four patients (7%) had previous pelvic u-radlatlon The hlstologc cntena were those estabhshed by Ober and Tovell [ 11, Noms and Taylor [2], and Kempson and Ban [3] and have been specifically discussed for this series of patients by Barwlck and LlVols~ [41 All hlstologlc material was revlewed for this study Twenty-five neoplasms were homologous and 29 were heterologous Using the clmlcal classlficatlon of the Internatlonal Federation of Gynecologists and Obstetnclans, there were 9 patients with stage IA disease, 31 patients with stage IB disease, 6 patients with clmlcal stage II disease, 4 patients with stage III disease, and 4 patients with stage IV disease Ten patients with clmlcal stage I disease, 1 with stage IA, and 9 with stage IB were found to have extrauterine disease at the time of surgical exploration In 3 of these 10 cases surgery was performed after preoperative pelvic u-radiation, m 2 patients after preoperative radium only, and m the remaining 4 surgical exploration was done as pnmary therapy The basis of management was surgical However, radlatlon therapy, mtracavltary brachytherapy with radium or cesmm or external beam u-radlatlon or both, was given to nearly all patients with early stage disease, usually pnor to surgical exploration Brachytherapy was mltlally admuustered by the method described by Morns et al [5] and recently Simon applicators were used for mtrauterme packmg Teletherapy was Bven using 4-, 8-, or 22-MV lmear accelerators with antenor-posterior opposmg fields, usually m dally fractions of 180 rad to a dose of 4000 to 5000 rad to the pelvis Four patients received paraaortlc n-radlatlon When the disease was found to have spread outside the uterus, selected patients received whole abdommal u-radlatlon, usually 2000 rad to the whole abdomen with a boost of 2500 rad to the pelvis Chemotherapy for recurrence reflected the use of the drugs consldered most effective during this period From 1974 these Included Adnamycm and cyclophosphannde and from 1979 various crs-platmum-based combmatlons Five patients received pnmary adjuvant chemotherapy, four with Adnamycm-cyclophosphamlde for 6-12 cycles and one with Adnamycm-cls-platinum for 12 cycles The dose schedule for Adnamycm-cyclophosphamlde was Adnamycm 50 mg/m* with cyclophosphamlde lG/m* given every 4 weeks provided that hematologlc, renal, and hepatlc parameters penmtted adnnmstratlon Adnamycm was momtored by senal left ventricular eJectIon fraction measurements [6] The dose schedule for Adnamycm, cls-platmum, and dlmethyltnazeno mndazole carboxannde @TIC) admmlstratlon was Adnamycm 50 mg/m*, cu-platinum 50 mg/m*, and DTIC 500 mg/m2 given every 4 weeks cu-Platinum was given with hydration and manmtol,

214

KOHORN

ET

AL

mg/m* given every 4 weeks czs-Platmum was gzven wzth hydratzon and manmtol, and Adnamycm cardzotoxzclty was momtored usmg senal left ventricular eJection fraction assessment RESULTS

In the group of patients wzth stage IA disease, 2 died with distant metastases and one patient, found to have metastases to the ovary at the time of pnmary surgery, remams chmcally free of dzsease at 24 months (Table 1) The latter patient received one course of combmatzon cu-platinum, Adnamycm, and cyclophosphamzde chemotherapy, refused further cytotoxzc chemotherapy, and has been maintained on tamoxzfen The remammg 6 patients wzth stage IA disease are chmcally dzsease free for 12-120 months (Table 1) The disease-free survival at 2 years m stage IA 1s thus 66% The patient with ovarian mvolvement and the 2 patients with recurrence had a heterologous hzstology whzle 5 of the 6 patients without recurrence had homologous tumors Thzrty-one patzents had chmcal stage IB dzsease Twenty-nine were explored and 9 (31%) had surgzcally more advanced dzsease than stage IB Szx of the latter 9 patients had heterologous tumors and 7 (78%) died 3 to 24 months followmg dzagnoszs (Table 2) One patient with mztlal fallopian tube mvolvement and subsequent medlastmal metastases had an objective response to Adrzamycm-czsplatinum chemotherapy (Table 2, No 9) and 1s alive wzth dzsease at 8 months The other survzvmg patient (Table 2, No 2) had extensive mtraabdommal disease, received chemotherapy with Adrlamycm and cyclophosphamlde and then czsplatinum, and 1s alive wzth disease at 24 months Of the 20 patients with surgzcally confirmed stage IB disease, 4 are alive and disease free, 10 died with metastases, and 2 patients are alive wzth disease at 36 and 44 months, respectively (Table 3) Four patients dzed from mtercurrent disease, 1 died of a pulmonary embolus 1 week after surgery, 1 of dzabetzc comphcatzons at 84 months, and 1 of heart fazlure at 24 months The latter 2 were chmcally free of tumor One patient died TABLE MIXED

No

Uterme length (cm)

MULLERIAN

Therapy RaS S RaS Ch(A-C) RaS Ch(A-C) SRRa RaSR RaS RaS RaS

TUMORS

1 OF UTERUS,

STAGE

IA

Outcome (months)

Hlstolo@c type

A (120) A (120) A (96) A (110) A (14) Lung metastases (12) A (120) Metastasis spme (14) Positwe ovary at initial surgery, metastases at (24)

Homologous Homologous Homologous Homologous Homologous Homologous Heterologous Heterologous Heterologous

Note Ra, mtrauterme radmm, R, radlatlon teletherapy, RA, radlatlon of paraaortlc ports added, S, surgery-hysterectomy and salpmgo-oophorectomy, S + , radxal surgery, A, ahve, D, died, Ch, chemotherapy, A-C, Adnamycm-cyclophosphamlde, APD, Adnamycm, cwplatmum, DTIC

1 2 3 4 5 6 1 8 9

10 14 10 12 12

9 Mass Mass

TUMORS

S RS RaS S RaRS SCh(CAP, VP-16) RS RaRS S

Primary therapy

MULLERIAN

* Controlled disease for 60 months Note Abbrevlatlons as m Table 1

No

Uterme size (cm)

MIXED

TABLE 2 IB, WITH

STAGE

Pelvis Pelws Aortlc node Omentum, diaphragm Aortlc nodes Abdommal masses Pelvis Diaphragm Tube

Site of Extrauterme disease

OF UTERUS,

DISEASE

Therapy

FOUND

Cytoxan, porphyromycm Refused RaR, medlastmal mass, APD 50% response

RRa” R provera R VAC APD

EXTRAUTERINE

D D D D D A D D A

(3) (13) (5)

(6) (24)

(10) (14) (3)

(62)

Survival (months)

AT SURGERY

Homologous Homologous Homologous Homologous Heterologous Heterologous Heterologous Heterologous Heterologous

Hlstologlc type

5

g 2 E

5 g

$u 5

2 8 g

F: E F z

5

g

SC s-4

10 10 10 -

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

14

12 -

20 14

15

12 20

-

(weeks)

RaS S RaSR RRaS RRaS SR SR RSCh(A-C) SR S(prev R) RaRS RRaSCh(A-C) RaRS RaRSb RS RS RaRaS RaRaS RaS S

Primary therapy

-

-

-

6 14 18 12 18 20 25 14 34 -

18 15 18 -

Abdomen Pelvis Vagina -

Abdomen Lung Lung Abdomen Abdomen Abdomen Lung Ascites Lung -

-

Time to recurrence

-

Site of recurrence

Homologous Homologous Homologous Homologous Homologous Homologous Homologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous Heterologous

Hmtologm type

One IS alive at 5 months and the other died at 2

A (120) A (24) D (20) D (12) D (25) (10) D WI A (W A (120) D (7) D (14) D (18) D W3) D (26) D (36) D (33) A (36) A (43) D (24) (1 week)

Outcome (months)

EXPLORATION"

AraC Actmomycm, CCNU APD Provera Megace Tamoxlfen CCF, aged 90 Pulmonary embolus

-

Provera Cytoxan Methotrexate Colon necrosis Diabetic sepsis

-

RX

AT SURGICAL

Note Abbrevlatlons as m Table 1 * Two patients were not explored, received radlatlon only, and are excluded from this Table months of heart frulure These patients are therefore not assessable for therapy response b Count as 5-year and 2-year Surv‘vLvors,respectively

13 9

-

15 10

10

9 10

km)

No

Utenne size

TABLE 3 MIXED MULLEI~IAN TUMORS OF THE UTERUS, STAGE IB, CONFIRMED

F

2

6 8 g

MIXED MULLERIAN

TUMORS

RADIATION/CHEMOTHERAPY

217

of radlatlon necrosis of the colon at 10 months No evidence of cancer was found at the time of colectomy Two patients received radiation only and their stage was not confirmed surgically (Table 3) The 2-year disease-free survival for stage IB disease confirmed followmg surg& exploration 1s therefore 20% (4/19), whde the overall 2-year survival for all chmcal stage IB cases IS 21% (6/29) (the patlent with colomc necrosis needs to be counted as a therapeutic death) Two of the patients survlvmg had homologous tumors and 2 had heterologous tumors Nme of 15 patients with recurrence had heterologous tumors and 3 had homologous tumors Six patients had stage II disease by virtue of hlstologlcally confirmed cervix mvolvement (Table 4) In none of these 6 was the cervix mvolvement advanced though It was chmcally vlslble m two All 6 patients were treated by radmm, radiation, and surgery, and 1 patient received primary adJuvant chemotherapy Two patients are disease free at 38 and 51 months One had a homologous tumor, and the other tumor was heterologous Recurrence m the 4 patients who died appeared as distant metastases at 3, 6, 14, and 24 months, respectively The 8 patients with stage III and IV disease died m 4 to 24 months One patient with stage III disease developed a node metastasis to the neck and received lo-month chemotherapy with cu-platmum, Adnamycm, and DTIC when progression occurred Also, 2 patients with extrapelvlc tumor received slmdar chemotherapy for 10 and 15 months, respectively (the latter patient came to second-look surgery which was posltlve for tumor) There was no greater frequency of heterologous tumors among those patients with stage II, III, and IV disease Among 29 patients with surgically confirmed stage I and II disease, 83% of recurrences appeared wlthm 2 years of dlagnosls, with a mean of 16 months (SD 7 months), while only 2 patients developed recurrences later at 25 and 34 months, respectively Table 5 shows the site of recurrence with surgically confirmed stage I and II disease m patients who had preoperative or postoperative radlatlon therapy Seventeen patients had both mtracavltary and external beam radlatlon to the pelvis and 2 patients received external beam radlatlon only Of these 19 patients, 3 developed pelvic recurrence (16%) Five patients received adJuvant chemotherapy for 6 months to 1 year (2 stage IA, 2 stage IB, and 1 stage II) m assoclatlon with primary radlatlon and surgical TABLE MIXED

No

Utenne size (cm) (weeks)

1 2 3 4 5

7 9 9 12 95

6

10 Note

MULLERIAN

TUMORS

Therapy RRaS RaRS RaRS RRaS RRaS

14

Abbrevlatlons

4 OF THE UTERUS,

RRaSCh(PA x 12) as m Table 1

Recurred A (51) Recurred Recurred Recurred treated A (38)

STAGE

II

Outcome (months)

Hlstologlc type

pelvis (24)

Homologous Homologous Homologous Homologous Heterologous

lung (14) brain (14) abdomen nodes (3) RT + controlled (14)

Heterologous

218

KOHORN

TABLE SITE OF RECURRENCE

OF MIXED

MULLERIAN FOLLOWING

ET

AL

5

TUMOR OF THE UTERUS, RADIATION THERAPY

STAGES

I AND

II

(SURGICAL),

Recurrence Therapy Radium + external beam Radmm only” Radlatlon (no radmm) Totals (%)

No of patients

Pelvic

Abdomen

Distal

17 8 2

3 0 0

5 1 0

6 1 1

29

3 (10)

6 (21)

8 (2%

’ Five Stage IA and three Stage IB less than 10 cm

management Four of these 5 patients (80%) are disease free for 60, 60, 96, and 38 months, respectively Twenty-five patients with stage I or II disease did not receive adJuvant chemotherapy and 7 of these survive disease free (28%) Nmeteen of these 25 patients with stage I and II disease received radlatlon therapy, 5 are disease free, 1 1s alive with disease, and 13 died, a disease-free survival of 26% Eight patients received platmum-based combmatlon chemotherapy for recurrence or for advanced disease found at surgery Six of these patients showed either ObJective response or lack of cancer progresslon for 4 to 24 months DISCUSSION Several recent studies have provided slgmficant mformatlon concerning the prognostlc features and therapeutic results with mlxed mullenan tumors of the uterus [7-121 It has been customary to study all sarcomas of the uterus as one entity because of the relatively small numbers wlthm any one series Smce lelomyosarcoma confined to the uterus appears to have a better prognosis than mixed mesodermal tumors and stromal sarcomas [9], their mcluslon may distort the findings More recent reports have therefore confined then studies to one particular hlstopatholo@c category, and the present report concerns mured mullenan tumors only This entity 1s now well described from a pathologic point of view and the hlstologlcal cntena have become well estabhshed [l-4] The present study finds similar chmcal presentation, age Incidence, and epldemlologlcal assoclatlons compared to previous studies [7,9,11,12] The tumor 1s found mamly m the seventh decade and the length of history 1s usually short Although Fehr and Prem [I31 considered that radiation may play a significant role m the etiology of these neoplasms, Norris and Taylor [2] found only a 12% assoclatlon, Peters et al [7] a 15% assoaatlon, Bartslch et al [14] a 5% assoaatlon, and the present series shows a 7% assoclatlon As m the previous study from Yale the data suggest that heterologous tumors have a worse prognosis However, this was evident mainly m the finding that, m chmcal stage I and II patients, surgically advanced disease and recurrence was associated with a slgmficantly higher frequency of heterologous tumors (67%) Forty-four of the 46 patients with chmcal stage I and II disease were explored

MIXED

MULLERIAN

TUMORS

RADIATION/CHEMOTHERAPY

219

More extensive disease than anticipated was found at the time of surgery m 10 patients (23%) This agrees with the findings m other reports Whether exploratory surgery should be preceded by radiation therapy, either m the form of intrauterine brachytherapy or teletherapy to the pelvis, remains controversial DlSala er al [ll], Perez et al [IO], Salazar et al [9], and Badlb et al [15] appear to support preoperative u-radiation Perez et al [lo] found a correlation between depth of myometnal mvaslon and prognosis, as patients who had no myometnal mvaslon had a uniformly good survival At Yale-New Haven Medical Center, the treatment plan mandated preoperative mtracavltary radlatlon and external beam radiation therapy, and only a few patients, m whom the diagnosis was not recognized prior to hlstologlc venficatlon of the tumor, were treated by pnmary surgery As there was usually a significant planned Interval between the brachytherapy and surgical exploration, the advantage of lmmedlate hlstologlc exammatlon of the uterus was not available Tumor present ongmally m the excised specimen may have been destroyed by the therapy When there was residual tumor after radiation, 2 of 20 patients survived 2 years, when no tumor was found, 10 of 14 survived From Tables 1-4, It appears that the small uterus with a less than IO-cm cavity size was associated with a better prognosis The present data appear to support the use of preoperative u-radlatlon m patients with mixed mullenan tumors of the uterus, m that only 3 of 17 patients (17 6%) who received both mtracavltary radiation and external beam u-radiation to the pelvis developed pelvic recurrences (Table 5) This frequency IS similar to that found by Perez er al [IO] However, 5 of these patients (29 4%) developed mtraabdommal metastases, and 6 (35 2%) developed distant metastases The disease-free survival for the entire group was only 18% The 8 patients who received preoperative mtracavltary radlatlon and no external beam radiation appeared to have fared better They had a survival rate of 75%, however, 5 of the 8 were stage IA disease and the other two survivors had a uterus less than 10 cm m length It IS of interest that 3 of the survivors also had adJuvant chemotherapy The treatment protocol of this series precludes comparison with patients who were treated with only surgery, for few were so treated Radiation therapy thus appears to be associated with a reduction m local recurrence without leading to slgmficantly Improved long-term survival This agrees with the findings of Peters et al [7], Perez et al [IO], and DlSala et al [ill It should be noted that the patient who developed radlatlon damage to her colon which led to her death was only one of two such radiation comphcatlons among more than 700 patients treated at Yale-New Haven Medlcal Center for uterme malignancy with external beam radiation during the time interval of this study Several reports of chemotherapy m mixed mullerlan tumors of the uterus have shown dlsappomtmg results [6,17], though Paver et al [18] found that a combmatlon of cyclophospharmde, Adnamycm, DTIC, and vmcnstme gave encouragmg results Omura et al [19] compared Adnamycm alone with Adnamycm and DTIC m patients with advanced or recurrent uterine sarcomas With mixed mullenan tumors the response rate was 11% for homologous tumors with either regimen while with heterologous tumors there appeared to be better response with com-

220

KOHORN ET AL

bmatlon Adrlamycm and DTIC (27 versus 8%) Lung metastases responded more frequently to combmatlon chemotherapy Seltzer et al [201 recently reported that 4 of 5 patients given cw-platinum and Adnamycm for metastatlc uterme sarcoma showed ObJeCtlVe response Two responses were complete no response was sustained In the present series, 8 patients were treated with chemotherapy for recurrence or for surgically advanced disease One patient 1s remarkable for the fact that she had mlcroscoplc mvolvement of the ovary, had one course of cw-platinum, Adnamycm, and DTIC chemotherapy, refused further cytotoxlc chemotherapy, and has now been mamtamed on tamoxlfen for 24 months without chmcal evidence of recurrence Another patient who was found to have advanced mtraabdommal disease at the time of laporotomy for an apparent stage IB tumor was mltlally treated with cyclophosphamlde and Adnamycm, then with CISplatinum and VP-16, and 1s ahve with disease at 24 months One patlent had an objective partial response to chemotherapy with Adnamycm, czs-platinum, and DTIC which has so far been mamtamed for 4 months Three patients with metastases to lung or mtraabdommal disease received Adrlamycm and CISplatinum chemotherapy for 12 to 15 months before there was chmcal progression of disease These data suggest that some patients with mixed mullerlan tumors may demonstrate wgmficant response to chemotherapy and that platinum-contimng chemotherapeutic regimens have actlvtty Response does not appear to be related to the hlstologlc subtype of tumor Five patients were treated by combmatlon of radlatlon, surgery, and adJuvant chemotherapy conslstmg of Adrlamycm and cyclophosphamlde for 6 months m 4 patients and with as-platinum and Adrlamycm m 1 patient with stage II disease Four of these 5 patients are alive and disease free from 36 months to 5 years (80%) Of the 25 patients with surgically proven stage IB disease who did not receive adjuvant chemotherapy, only 8 are alive (28%) Since 3 of the patients treated with adjuvant chemotherapy had stage IA tumors, these data may not be statlstlcally slgmficant Buchsbaum et al [211 consldered that there may be a place for adJuvant chemotherapy followmg surgical exicislon of early stage uterme sarcomas Omura et al [22] reported the use of adjuvant Adnamycm m surgically confirmed stage I and II uterme sarcoma and found no statlstlcally significant advantage for the use of single agent Adnamycm Nevertheless, only 5 of 19 (26%) heterologous tumors recurred when Adnamycm was given while 13 of 27 (48%) recurred when no adjuvant therapy was offered From these experiences with adjuvant chemotherapy and chemotherapy for recurrent disease there thus appears to be adequate mdlcatlon for a chmcal tnal of czs-platmumcontaining combmatlon chemotherapy as addltlonal pnmary adjuvant therapy m patients with totally excised mixed mullerlan tumors of the uterus REFERENCES 1 Ober, W B , and Tovell, H M M Mesenchymal sarcomas of the uterus, Amer J Obstet Gynecol 77, 246-268 (1959) 2 Noms, H J , and Taylor, H B Mesenchymal tumors of the uterus III A chtucal and pathologic study of 31 carcmosarcomas, Cancer 19, 1459-1465 (1966) 3 Kempson, R L , and Ban, W Uterme sarcomas Classification, dlagnosls, and prognosis, Human Puthol 1, 331-349 (1970)

MIXED

7 8

9 10 11 12 13 14 15 16 17 18 19 20 21 22

MULLERIAN

TUMORS

RADIATION/CHEMOTHERAPY

221

Barwlck, K W , and LIVOISI, V A Malignant mixed mullenan tumors of the uterus, Amer J Surg Pathol 3, 125-135 (1979) Moms, J M , Chang, C H , and Page, V A radrum technic for treatment of cancer of the cervix, Radrology, 84, 849-858 (1965) Schwartz, P E , Berger, H J , Kohom, E I , and Zaret, B L Senal left ventricular ejection fraction determmatlons to monitor doxorublcm cardlotoxlclty m gynecologic mahgnancles, m Proceedmgs, ASCO C272, 71 (1982) Peters, W A , Kumar, N B , Fleming, W P , and Morley, G W Prognostic features of sarcomas and mixed tumors of the endometnum, Obster Gynecol 63, 550 (1984) Spanos, W J , Wharton, J T . Gomez, L et al Malignant mixed mullenan tumors of the uterus, Cancer 53, 311-316 (1984) Salazar, 0 M , Bonfigho, T A , Patten, S F et al Uterme sarcomas Analysis of fmlures with special emphasis on the use of adjuvant radiation therapy, Cancer 42, 1161-1170 (1978) Perez, C A , A&m, F , Baglan, R J , et al Effects of lrradlatlon on mixed mullenan tumors of the uterus, Cancer 43, 1274-1284 (1979) DISala, P J , Castro, J R , and Rutledge, F N Mixed mesodermal sarcoma of the uterus, Obstet Gynecol 177, 632-636 (1976) Mortel, R , Nedwlch, A , Lewis, G C , ef al Malignant mixed mullenan tumors of the uterme corpus, Obstet Gynecol 35, 468-480 (1970) Fehr, P E , and Prem, K A Malignancy of the utenne corpus followmg !rradlatlon therapy for squamous cell carcmomd of the cervix, Amer J Obstet Gynecol 119, 685-692 (1974) Bartslch, E G , O’Leary, J A , and Moore, J G Carcmosarcoma of the uterus A SO-year review of 32 cases, Obstet Gynecol 30, 518-523 (1967) Badlb, A 0 , Vongtama, V , Kurohara, S S , and Webster, J H Radiotherapy m the treatment of sarcomas of the corpus uteri, Cancer 4, 724-729 (1969) Hamugan, E V , Freedman, R S , and Rutledge, F N AdJuvant chemotherapy m early uterme sarcoma, Gynecol Oncol 15, 56-64 (1983) Rver, M S , Barlow, J J , Lele, S B , and Yazlgl, R Adnamycm m localized and metastatlc utenne sarcomas, J Surg Oncol 12, 263-265 (1979) Rver, M S , DeEuhs, T G , Lele, S B , and Barlow, J J Cyclophosphamlde, vmcnstme, Adnamycm, and dimethyl-tnazeno lmldazole carboxamlde (CYVADIC) for sarcomas of the female genital tract, Gynecol Oncol 14, 319-323 (1982) Omura, G A , Major, F J , Blessing, J A , et al A randomized study of Adnamycm with and without dlmethyl tnazenolmldazole carboxamlde m advanced uterme sarcomas, Cancer 52, 626-632 (1983) Seltzer, V , Kaplan, B , Vogel, S , and Spltzer, M Doxomblcm and czs-platm m the treatment of advanced mixed mesodermal utenne sarcoma, Cancer Chemother Rep 68, 1389-1390 (1984) Buchsbaum, H J , Llfshltz, S , and Blythe, J G Prophylactic chemotherapy m stages I and II utenne sarcoma, Gynecol Oncol 8, 346-348 (1979) Omura, G A , Blessing, J A , Major, F , and Sdverberg, S A randomized tnal of Adnamycm versus no adjuvant chemotherapy m stage I and II utenne sarcomas, m CIznzcal trzals Gynecologzcal tumors ASCO 2, C-580 (1983) [Abstract]