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Cisplatin and Adriamycin combination chemotherapy for uterine stromal sarcomas and mixed mesodermal tumors
GYNECOLOGIC ONCOLOGY 34,
323-327 (1989)
Cisplatin and Adriamycin Combination Chemotherapy for Uterine Stromal Sarcomas and Mixed Mesodermal Tumors’ WILLIAM A. PETERSIII, M.D. ,* SAUL E. RIVIUN, M.D., MICHAEL R. SMITH, M.D., AND DONALD E. TESH, M.D. Puget Sound Oncology Consortium, 1229 Madison, Suite 1050, Seattle, Washington 98104
ReceivedNovember 23, 1988 Twenty-eight patients with a uterine stromal sarcoma or mixed mesodermal tumor were treated with cisplatin 100 mg/m’ and Adriamycin 45-60 mg/m*, 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 previously established poor prognostic features. CMthe 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 S-year survival of 75% in these highrisk 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. Q 1989 AC&AC RSS,
histologic appearances and multiple conflicting classification systems, it has been difficult to reach conclusions about the effect of various treatments on survival [1,2]. With endometrial and endocervical tumors, recent studies have shown that there are few differences between pure stromal sarcomas and mixed mesodermal tumors (homologous or heterologous) [2-41. Pure leiomyosarcomas arise within the myometrium and their clinical behavior appears to differ from that of tumors arising from the endometrial or endocervical stroma. Among tumors arising within the endometrium, the prognosis is related closely to the extent of disease found at the time of initial surgery. For patients with disease limited to the uterus, the prognosis is based almost entirely on the depth of myometrial invasion [2-61. The presence of malignant cells in the cytologic washings also appears to be a poor prognostic feature [7]. Patients with recurrent or metastatic tumor have had a uniformly poor prognosis and a benefit of radiation therapy or chemotherapy has not been demonstrated. This paper reports the experience of the Puget Sound Oncology Consortium (PSOC) with cisplatin/Adriamycin combination chemotherapy in 11 patients with metastatic or recurrent tumors as well as 17 patients treated with adjuvant therapy. METHODS AND MATERIALS
Inc.
Sarcomas are a rare and highly malignant group of neoplasms arising throughout the female genital tract. The uterine fundus remains the most common site of origin, but similar tumors arise in the ovary, fallopian tubes, cervix, and vagina. Because of a vast array of ’ Presented at the annual meeting of the Society of Gynecologic Oncologists, Maui, Hawaii, February 5-9, 1989. * TO whom correspondence should be addressed.
Between 1981 and 1988, 28 patients were treated with combination chemotherapy at member institutions of the Puget Sound Oncology Consortium (PSOC) for mixed mesodermal tumor or stromal sarcoma arising in the uterus. Group I consisted of 11 patients treated with advanced primary or recurrent tumor. None of the patients had received prior chemotherapy or irradiation. They received cisplatin 100 mg/m* and Adriamycin 4560 mg/m* every 3 weeks for six cycles or until there was evidence of tumor progression. 323 0090-8258/89 $1.50 Copyright 0 1989by AcademicPress,Inc. All rights of reproductionin any form reserved.
324
PETERS ET AL.
Seventeen patients were treated on a formal protocol with adjuvant therapy (group II). Patient eligibility for this study included invasion greater than one-third of the myometrium and/or documented involvement of the adnexa, the pelvic lymph nodes, and/or the periaortic lymph nodes with complete resection of all gross tumor. Full surgical staging was encouraged prior to entry in this protocol but some patients were operated on prior to referral and were entered without these data. Patients were treated with a combination of cisplatin 100 mg/m* and Adriamycin 60 mg/m* for patients less than. or equal to age 65 or 45 mg/m* for patients greater than 65 given every 3 weeks for a total of six doses. Patients treated on the adjuvant protocol then received 45-50 Gy of external irradiation to the pelvis for over 5 weeks. Patients with documented periaortic nodal metastases received extended-field irradiation with 45 Gy to encompass the periarotic nodes. Life-table survival probabilities were projected using the method of Kaplan and Meier [8]. RESULTS Group I consists of the 11 patients with advanced primary or recurrent neoplasms. In all 11 patients there was measurable disease. The clinical data for these patients are outlined in Table 1. Eight of the eleven (73%) eva-
luable patients have had a response. Three patients underwent a second-look procedure at the completion of chemotherapy. Two patients had undergone sigmoid resection as part of their primary procedure; one had colostomy closure at the time of second-look. All three patients surgically had no evidence of disease and are alive and well IO-31 months from initial diagnosis. Group II consists of 17 patients with no gross residual disease who were treated with adjuvant therapy after primary surgery. These patients were selected for therapy based on previously established poor prognostic features. Fourteen of these patients had undergone full surgical staging, including 12 patients with endometrial tumors and 2 with endocervical tumors. Five patients had documented pelvic nodal metastases, and 2 patients had documented periaortic nodal metastases. All 14 patients had invasion to the outer two-thirds of the myometrium or cervix and 3 patients had invasion to the serosa. Two patients had metastatic disease in the parametrium. Five patients had positive peritoneal washings, and 5 patients had negative washings; washings were not done in the other 4 patients. The other three patients (in group II) were treated with the same protocol but were referred after primary surgery by a general gynecologist and did not have full surgical staging. Two of these three patients had primary cervical tumors and one patient was suspected of having
TABLE
1
Clinical Data on 11 Patientswith AdvancedPrimary or Recurrent Disease Patient
Age
Tumor type
1. M.B.
82
2. A.L.
66
3. L.R.
86
4. C.A.
51
5. E.R.
70
6. D.N.
77
Heterologous MMT,” endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endometrium Homologous MMT, endometrium Homologous MMT, endometrium
7. G.F.
70
8. J.J.
46
9. E.B.
68
10. K.A.
61
11. P.H.
60
Heterologous MMT, endometrium Stromal sarcoma, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endometrium
Disease site
Result
Therapy
Status
Diffuse abdominal
2
Progression
DOD 4 months
Liver, pelvic and periaortic nodal Spleen, lung
6
CR x 8 months
DOD 11 months
2
CR x 4 months
DOD 9 months
Diffuse abdominal
6
NED 29 months
Diffuse abdominal
6
Diffuse abdominal Ascites Supraclavicular node Vagina
1
CR x 29+ months (surgical) CR x 31+ months (surgical) Progression
2
CR
NED 20 months
x
20+ months
NED 31 months DOD 2 months
Diffuse abdominal Lung Diffuse abdominal Lung Diffuse abdominal
6
CR x II+
6
Disease stable x 6 months CR x 10 months
DOD 10 months
Diffuse abdominal
6
CR x 10 months (surgical)
NED 6 months
6
months
’ MMT, mixed mesodermal tumor; CR, complete response; DOD, dead of disease; NED, no evidence of disease.
NED 11 months
DOD 13 months
COMBINATION
gross residual disease in the pelvis by the treating oncologist, although this was contrary to the impression of the operating surgeon. All three patients were treated because of invasion to the outer one-half of the cervix or myometrium. Table 2 summarizes the response to therapy and clinical outcome in these 17 patients treated in an adjuvant setting. Four patients had grade 3 or 4 hematologic toxicity and had dose reduction in subsequent cycles. There were no documented episodes of sepsis. Four patients had grade 3 or 4 nausea and vomiting. There were no other cases of grade 3 or 4 toxicity. Deviations from protocol were encountered in eight patients. Two patients refused further therapy after only two cycles of chemotherapy; one patient discontinued therapy after
325
CHEMOTHERAPY
four cycles and another after five cycles. A fifth patient developed abnormal left ventricular function without clinical evidence of congestive heart failure following two cycles of therapy. The Adriamycin was discontinued. She received two additional cycles of cisplatin alone but developed renal dysfunction and began her pelvic irradiation without further chemotherapy. One additional patient completed her chemotherapy, but did not receive irradiation. In all, six patients elected not to receive radiation therapy. Four of the seventeenpatients have relapsed and died. The median survival in these patients is 23.5 months. One patient died 17 months following treatment with sepsis and the sequelae of a cerebrovascular accident. Although she had been treated for radiation enteritis, the
TABLE 2 Clinical Data and Stagingin 17 PatientsReceivingAdjuvantTherapy Patient
Age
1. B.A.
59
2. B.D.
64
3. P.W.
66
4. D.B.
59
5. R.D.
76
6. M.P.
76
7. C.O.
69
8. M.R.
75
9. A.G.
64
10. T.C.
38
11. NC.
61
12. C.Q.
40
13. A.M.
65
14. R.S.
64
15. B.M.
76
16. A.R.
74
17. D.B.
71
Pelvic nodes
Periaortic nodes
Negative
Negative
Serosa
Positive
Negative
Outer third
Negative
Negative
Outer third
Negative
Negative
Middle third
Positive
Negative
Outer third
-
None
NED 70 months
Negative
Unknown
Serosa
-
DOD 26 months
Positive
Negative
Outer third
Positive washings
5 cycles of chemotherapy, then refused further therapy None
Negative
Negative
Serosa
Positive washings
DOD 24 months
Unknown
Positive
Outer third
-
2 cycles of chemotherapy, then refused further therapy None
Unknown
Unknown
Outer third
-
Homologous MMT, endocervix
Unknown
Unknown
Outer third
-
Stromal sarcoma, . endometrium Heterologous MMT, endocervix
Unknown
Unknown
Middle third
-
Unknown
Positive
Middle third
-
Positive
Negative
Serosa
Parametrial involvement
Positive
Negative
Other third
Positive washings
Negative
Negative
Other third
Negative
Negative
Outer third
Tumor type Homologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Homologous MMT, endometrium Homologous MMT, endometrium Homologous MMT
Heterologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endocervix
Heterologous MMT, endocervix Homologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium
Depth invasion
Treatment deviation
Other Positive washings
Parametrial lymphatic and cervix involvement -
Positive washings
’ MMT, mixed mesodermal tumor; NED, no evidence disease; DOD, dead of disease; d/c, discontinued.
Outcome
None
NED 59 months
None
Died 28 months perforated diverticulum NED 81 months NED 71 months
4 cycles of chemotherapy, then refused further therapy Adriamycin d/c after 2 cycles, cisplatin d/c after 4 cycles None
DOD 23 months
NED 90 months NED 36 months DOD 9 months NED 45 months
5 cycles of chemotherapy, then refused further therapy None
NED 38 months
4 cycles of chemotherapy 2 cycles of chemotherapy, then refused further therapy 6 cycles chemotherapy, no irradiation
NED 34 months
NED 36 months
NED 26 months NED 12 months
326
PETERS ET AL.
surgical findings and subsequent autopsy were more consistent with a perforated diverticulum. This patient had initially presented with extensive pelvic nodal metastasis and her postmortem examination was completely negative for cancer. The other 12 patients are alive and disease free with a median survival of 42 months. Using Kaplan-Meier life-table analysis, there is a 75% projected 5-year survival for group II. Of the seven patients with documented nodal involvement, one patient died with recurrent disease at 23 months, one patient died of 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 alive and disease free more than 5 years after diagnosis. Both patients with documented periaortic nodal metastases are still disease free. Table 3 lists relapses by the number of cycles of chemotherapy patients received in group II. There is a suggestion that survival is diminished with receiving less than four cycles of therapy. There were two relapses in the 11 patients receiving planned irradiation and two relapses in the 6 patients who refused their irradiation.
adjuvant radiation therapy; however, the overall survival rate has not been improved with radiation therapy as patients succumb to systemic disease. Published reports of chemotherapy in patients with metastatic disease have shown a 6-25% response rate with Adriamycin as a single agent [ 12-151. Cisplatin as a single agent had an 18% response rate in heavily pretreated patients [16]. Adriamycin plus DTIC, Adriamycin plus Cytoxan, and VAC have produced similar results [12,15,17-191. In general, responses have been of short duration. Recent reports from Kohorn et al. and Seltzer et al. suggested that the combination of Adriamycin and cisplatin (with or without Cytoxan) was an active combination in patients with metastatic mixed mesodermal tumors [20,21]. A 33% response rate was reported by Grosh et al. to Hexa-CAP [22]. In their patients, cisplatin was given at 60 mg/m’. Piver et al. reported a 20% response rate to DTIC combined with conventional-dose cisplatin and a 50% response rate when cisplatin was given at a dose of 20 mg/m2 daily for 5 days [231. We have had similar experience in treatment of patients with metastatic uterine and ovarian mixed mesodermal tumors and this led to the initiation of a trial of cisplatin and Adriamycin in an adjuvant setting [24,25]. DISCUSSION Most reports with adjuvant chemotherapy have been Endometrial and cervical sarcomas and mixed tumors disappointing. A randomized prospective trial carried out have carried a dire prognosis. A recent review from the by the Gynecologic Oncology Group showed that the University of Michigan showed that in patients with stage single agent, Adriamycin, at a dose of 60 mg/m2, given I and II endometrial tumors, the depth of myometrial every 3 weeks for a total of eight cycles, was not effective invasion was the strongest predictor of survival [2]. in reducing the recurrence rate with endometrial sarThere were no recurrences among patients with disease comas or leiomyosarcomas of the myometrium [26]. Retlimited to the endometrium among patients who had full rospective studies, reported by Hannigan et al. and by surgical staging. Among patients with invasion of the Piver et al., who examined single-agent Adriamycin or outer one-third of the myometrium, the recurrence rate combination therapy with Adriamycin and DTIC, failed approached 100%. When tumor invaded the inner third to show a survival advantage [11,13]. Buchsbaum et al. of the myometrium, survival of 5 years was approxi- and Van Nagell et al. have suggested an improvement mately 75%, and when the tumor invaded the middle in survival with postoperation chemotherapy employing third, survival was approximately 50%. VAC. Their studies are difficult to evaluate because they Experience with adjuvant radiation therapy has been combined patients with mixed mesodermal tumors and extremely discouraging [2,3,6,9,11]. Most studies have patients with leiomyosarcomas and they did not differshown a decrease in the pelvic recurrence rate following entiate between high- and low-risk patients [27,28]. Our data, as well as those of Kohorn et al., would suggest that combined therapy with Adriamycin and cisTABLE 3 platin improves the prognosis of patients with high-risk Recurrences by Number of Cycles of Chemotherapy endometrial and endocervical stromal sarcomas or mixed in Group II mesodermal tumors. Patients with documented positive Relapses/total patients treated Number of cycles nodes were much more likely to continue their chemotherapy and to receive their irradiation, which may ex2 213 plain their excellent survival. There were fewer recur3 4 rences in our patients who received radiation therapy. 013 5 l/3 However, patients who discontinued chemotherapy prior 6 118 to completion of six cycles were much more likely to Total 4117 refuse radiation therapy, making it difficult to evaluate
COMBINATION
the benefit of radiation therapy from our data. Whether a protocol that completely eliminated the use of irradiation would be equally effective is a matter of conjecture at present. REFERENCES 1. Ober, W. B. Uterine sarcomas: Histogenetics and taxonomy, Ann. NY Acad. Sci. 75, 568-585 (1959). 2. Peters, W. A., III, Kumar, N. B., Fleming, W. P., and Morley, G. W. Prognostic features of sarcomas and mixed tumors of the endometrium, Obstet. Gynecol. 63, 550-556 (1984). 3. Lotocki, R., Rosenshein, N. B., Grumbine, F., Dillon, M., Parmley, T., and Woodruff, J. D. Mixed mullerian tumors of the uterus: Clinical and pathologic correlations, Int. J. Gynecol. Obstet. u), 237-243 (1982). 4. Salazar. 0. M.. Bontialio, T. A., Patten, S. F., er al. Uterine sarcomas: Natural’histot$, treatment and prognosis, Cancer 42, 11521160 (1978). 5. Vongtama, V., Karlen, J. R., Piver, S. M., Tsukada, Y., and Moore, R. H. Treatment results and prognostic factors in stage I and II sarcomas of the corpus uteri, Amer. .I. Roentgenol. Radium Ther. Nucl. Med. 126, 139-147 (1976). 6. Barwick, K. W., and Livolsi, V. A. Malignant mixed mullerian tumors of the uterus, Amer. J. Surg. Pathol. 3, 125-135 (1979). Geszler, G., Szpak, C. A., Harris, R. E., Creasman, W. T., Barter, J. F., and Johnston, W. W. Prognostic value of peritoneal washings in patients with malignant mixed mulletian tumors of the uterus, Amer. J. Obstet. Gynecol. 155, 83-89 (1986). Kaplan, E. L., and Meier, P. Nonparametric estimation from incomplete observations, J. Amer. Stat. Assoc. 53, 457-481 (1958). Perez, C. A., Askin, F., Baglan, R. J., et al. Effects of irradiation on mixed mullerian tumors of the uterus, Cancer 43, 1274-1284 (1979). 10. Chuang, J. T., Van Velden, I. J., and Graham, J. B. Carcinosarcoma and mixed mesodermal tumor of the uterine corpus, Obstet. Gynecol. 35, 769-780 (1970). 11. Hannigan, E. V., Freedman, R. S., and Rutledge, F. N. Adjuvant chemotherapy in early uterine sarcoma, Gynecol. Oncol. 15, 5664 (1983). 12. Omum, G. A., and Blessing, J. Chemotherapy of stage III, IV and recurrent uterine sarcomas: A randomized trial of Adriamycin vs Adriamycin + dimethyl-triazeno-imidazole carboxamide, Amer. Assoc. Cancer Res. Proc. 19, 26 (1978). 13. Piver, M. S., Barlow, J. J., Lele, S. B., and Yazig, R. Adriamycin in localized and metastatic uterine sarcomas, J. Surg. Oncol. 12, 263-265 (1979). 14. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with Adriamycin, Gynecof. Oncol. 16, 101-104 (1983).
CHEMOTHERAPY
15.Muss,
327
H. B., Bundy, B., Di Saia, P. J., ef al. Treatment of recurrent or advanced uterine sarcoma: A randomized trial of doxorubicin versus doxorubicin and cyclosphosphamide, Cancer 55, 1648-16S3 (1985). 16. Thigpen, T., Shingleton, H., Homesley, H., and Blessing, J. Phase II trial of cis-diaminedichloroplatimun (DDP) in treatment of advanced or recurrent mixed mesodermal sarcoma of the uterus, Proc. Amer. Sot. C/in. Oncol. 1, 110 (1982). 1, Omara, G. A., Major, F. J., Blessing, J. A., et al. A randomized study of Adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas, Cancer 52, 626-632 (1983). 18. Piver, M. S., De Eulis, T. G., Lele, S. B., and Barlow, J. J. Cyclophosphamide, vincristine, Adriamycin and dimethyl-triazenolimidazole carboxamide (CYVADIC) for sarcomas of the female genital tract, Gynecol. Oncol. 14, 319-323 (1982). 19. Hannigan, E. V., Freedman, R. S., Elder, K. W., and Rutledge, F. N. Treatment of advanced uterine sarcoma with vincristine, actinomycin-D and cyclophosphamide, Gynecol. Oncol. 15, 224229 (1983). 20. Seltzer, V., Kaplan, B., Vogl, S., and Spitzer, M. Doxorubicin and cisplatin in the treatment of advanced mixed mesodermal uterine sarcoma, Cancer Treat. Rep. 68, 1389-1390 (1984). 21. Kohom, E. I., Schwartz, P. E., Chambers, J. T., Peschel, R. E., Kapp, D. S., and Merimo, M. Adjuvant therapy in mixed mullerian tumors of the uterus. Gynecol. Oncol. 23, 212-221 (1986). 22. Grosh, W. M., Jones, H. W., Burnett, L. S., and Greco, F. A. Malignant mixed mesodermal tumors of the uterus and ovary treated with cisplatin-based combination chemotherapy, Gynecol. Oncol. 25, 334-339 (1986). 23. Piver, M. S., Lele, S. B., and Patsner, B. cis-Diamminedichloroplatinum plus dimethyl-dimethyltriazenoimidazole carboxamide as second- and third-line chemotherapy for sarcomas of the female pelvis, Gynecol. Oncol. 23, 371-375 (1986). 24. Peters, W. A., III, Bagley, C. M., and Smith, M. R., CA-125: Use as a tumor marker with mixed mesodermal tumors of the female genital tract, Cancer 58, 2625-2627 (1986). 25. Andersen, W. A., Young, D. E., Peters, W. A., III, Smith, E. B., Bagley, C. M., and Taylor, P. T. Platinum-based combination chemotherapy for malignant mixed mesodermal tumors of the ovary, Gynecol. Oncol. 32, 319-322 (1989). 26. Omura, G. A., Blessing, J. A., Major, F., and Silverberg, S. A randomized trial of adtiamycin vs no adjuvant chemotherapy in stage I and II uterine sarcomas, Proc. Amer. Sot. Clin. Oncol. 2, 149 (1983). 27. Buchsbaum, H. J., Lifshitz, S., and Blythe, J. G. Prophylactic chemotherapy in stages I and II uterine sacoma, Gynecol Oncol. 8, 346-348 (1979). 28. Van Nagell, J. R., Hanson, M. B., Donaldson, E. S., and Gallion, H. H. Adjuvant vincristine, dactinomycin and cyclophosphamide therapy in stage I uterine sarcomas, Cancer 57, 1451-1454 (1986).
323-327 (1989)
Cisplatin and Adriamycin Combination Chemotherapy for Uterine Stromal Sarcomas and Mixed Mesodermal Tumors’ WILLIAM A. PETERSIII, M.D. ,* SAUL E. RIVIUN, M.D., MICHAEL R. SMITH, M.D., AND DONALD E. TESH, M.D. Puget Sound Oncology Consortium, 1229 Madison, Suite 1050, Seattle, Washington 98104
ReceivedNovember 23, 1988 Twenty-eight patients with a uterine stromal sarcoma or mixed mesodermal tumor were treated with cisplatin 100 mg/m’ and Adriamycin 45-60 mg/m*, 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 previously established poor prognostic features. CMthe 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 S-year survival of 75% in these highrisk 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. Q 1989 AC&AC RSS,
histologic appearances and multiple conflicting classification systems, it has been difficult to reach conclusions about the effect of various treatments on survival [1,2]. With endometrial and endocervical tumors, recent studies have shown that there are few differences between pure stromal sarcomas and mixed mesodermal tumors (homologous or heterologous) [2-41. Pure leiomyosarcomas arise within the myometrium and their clinical behavior appears to differ from that of tumors arising from the endometrial or endocervical stroma. Among tumors arising within the endometrium, the prognosis is related closely to the extent of disease found at the time of initial surgery. For patients with disease limited to the uterus, the prognosis is based almost entirely on the depth of myometrial invasion [2-61. The presence of malignant cells in the cytologic washings also appears to be a poor prognostic feature [7]. Patients with recurrent or metastatic tumor have had a uniformly poor prognosis and a benefit of radiation therapy or chemotherapy has not been demonstrated. This paper reports the experience of the Puget Sound Oncology Consortium (PSOC) with cisplatin/Adriamycin combination chemotherapy in 11 patients with metastatic or recurrent tumors as well as 17 patients treated with adjuvant therapy. METHODS AND MATERIALS
Inc.
Sarcomas are a rare and highly malignant group of neoplasms arising throughout the female genital tract. The uterine fundus remains the most common site of origin, but similar tumors arise in the ovary, fallopian tubes, cervix, and vagina. Because of a vast array of ’ Presented at the annual meeting of the Society of Gynecologic Oncologists, Maui, Hawaii, February 5-9, 1989. * TO whom correspondence should be addressed.
Between 1981 and 1988, 28 patients were treated with combination chemotherapy at member institutions of the Puget Sound Oncology Consortium (PSOC) for mixed mesodermal tumor or stromal sarcoma arising in the uterus. Group I consisted of 11 patients treated with advanced primary or recurrent tumor. None of the patients had received prior chemotherapy or irradiation. They received cisplatin 100 mg/m* and Adriamycin 4560 mg/m* every 3 weeks for six cycles or until there was evidence of tumor progression. 323 0090-8258/89 $1.50 Copyright 0 1989by AcademicPress,Inc. All rights of reproductionin any form reserved.
324
PETERS ET AL.
Seventeen patients were treated on a formal protocol with adjuvant therapy (group II). Patient eligibility for this study included invasion greater than one-third of the myometrium and/or documented involvement of the adnexa, the pelvic lymph nodes, and/or the periaortic lymph nodes with complete resection of all gross tumor. Full surgical staging was encouraged prior to entry in this protocol but some patients were operated on prior to referral and were entered without these data. Patients were treated with a combination of cisplatin 100 mg/m* and Adriamycin 60 mg/m* for patients less than. or equal to age 65 or 45 mg/m* for patients greater than 65 given every 3 weeks for a total of six doses. Patients treated on the adjuvant protocol then received 45-50 Gy of external irradiation to the pelvis for over 5 weeks. Patients with documented periaortic nodal metastases received extended-field irradiation with 45 Gy to encompass the periarotic nodes. Life-table survival probabilities were projected using the method of Kaplan and Meier [8]. RESULTS Group I consists of the 11 patients with advanced primary or recurrent neoplasms. In all 11 patients there was measurable disease. The clinical data for these patients are outlined in Table 1. Eight of the eleven (73%) eva-
luable patients have had a response. Three patients underwent a second-look procedure at the completion of chemotherapy. Two patients had undergone sigmoid resection as part of their primary procedure; one had colostomy closure at the time of second-look. All three patients surgically had no evidence of disease and are alive and well IO-31 months from initial diagnosis. Group II consists of 17 patients with no gross residual disease who were treated with adjuvant therapy after primary surgery. These patients were selected for therapy based on previously established poor prognostic features. Fourteen of these patients had undergone full surgical staging, including 12 patients with endometrial tumors and 2 with endocervical tumors. Five patients had documented pelvic nodal metastases, and 2 patients had documented periaortic nodal metastases. All 14 patients had invasion to the outer two-thirds of the myometrium or cervix and 3 patients had invasion to the serosa. Two patients had metastatic disease in the parametrium. Five patients had positive peritoneal washings, and 5 patients had negative washings; washings were not done in the other 4 patients. The other three patients (in group II) were treated with the same protocol but were referred after primary surgery by a general gynecologist and did not have full surgical staging. Two of these three patients had primary cervical tumors and one patient was suspected of having
TABLE
1
Clinical Data on 11 Patientswith AdvancedPrimary or Recurrent Disease Patient
Age
Tumor type
1. M.B.
82
2. A.L.
66
3. L.R.
86
4. C.A.
51
5. E.R.
70
6. D.N.
77
Heterologous MMT,” endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endometrium Homologous MMT, endometrium Homologous MMT, endometrium
7. G.F.
70
8. J.J.
46
9. E.B.
68
10. K.A.
61
11. P.H.
60
Heterologous MMT, endometrium Stromal sarcoma, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endometrium
Disease site
Result
Therapy
Status
Diffuse abdominal
2
Progression
DOD 4 months
Liver, pelvic and periaortic nodal Spleen, lung
6
CR x 8 months
DOD 11 months
2
CR x 4 months
DOD 9 months
Diffuse abdominal
6
NED 29 months
Diffuse abdominal
6
Diffuse abdominal Ascites Supraclavicular node Vagina
1
CR x 29+ months (surgical) CR x 31+ months (surgical) Progression
2
CR
NED 20 months
x
20+ months
NED 31 months DOD 2 months
Diffuse abdominal Lung Diffuse abdominal Lung Diffuse abdominal
6
CR x II+
6
Disease stable x 6 months CR x 10 months
DOD 10 months
Diffuse abdominal
6
CR x 10 months (surgical)
NED 6 months
6
months
’ MMT, mixed mesodermal tumor; CR, complete response; DOD, dead of disease; NED, no evidence of disease.
NED 11 months
DOD 13 months
COMBINATION
gross residual disease in the pelvis by the treating oncologist, although this was contrary to the impression of the operating surgeon. All three patients were treated because of invasion to the outer one-half of the cervix or myometrium. Table 2 summarizes the response to therapy and clinical outcome in these 17 patients treated in an adjuvant setting. Four patients had grade 3 or 4 hematologic toxicity and had dose reduction in subsequent cycles. There were no documented episodes of sepsis. Four patients had grade 3 or 4 nausea and vomiting. There were no other cases of grade 3 or 4 toxicity. Deviations from protocol were encountered in eight patients. Two patients refused further therapy after only two cycles of chemotherapy; one patient discontinued therapy after
325
CHEMOTHERAPY
four cycles and another after five cycles. A fifth patient developed abnormal left ventricular function without clinical evidence of congestive heart failure following two cycles of therapy. The Adriamycin was discontinued. She received two additional cycles of cisplatin alone but developed renal dysfunction and began her pelvic irradiation without further chemotherapy. One additional patient completed her chemotherapy, but did not receive irradiation. In all, six patients elected not to receive radiation therapy. Four of the seventeenpatients have relapsed and died. The median survival in these patients is 23.5 months. One patient died 17 months following treatment with sepsis and the sequelae of a cerebrovascular accident. Although she had been treated for radiation enteritis, the
TABLE 2 Clinical Data and Stagingin 17 PatientsReceivingAdjuvantTherapy Patient
Age
1. B.A.
59
2. B.D.
64
3. P.W.
66
4. D.B.
59
5. R.D.
76
6. M.P.
76
7. C.O.
69
8. M.R.
75
9. A.G.
64
10. T.C.
38
11. NC.
61
12. C.Q.
40
13. A.M.
65
14. R.S.
64
15. B.M.
76
16. A.R.
74
17. D.B.
71
Pelvic nodes
Periaortic nodes
Negative
Negative
Serosa
Positive
Negative
Outer third
Negative
Negative
Outer third
Negative
Negative
Middle third
Positive
Negative
Outer third
-
None
NED 70 months
Negative
Unknown
Serosa
-
DOD 26 months
Positive
Negative
Outer third
Positive washings
5 cycles of chemotherapy, then refused further therapy None
Negative
Negative
Serosa
Positive washings
DOD 24 months
Unknown
Positive
Outer third
-
2 cycles of chemotherapy, then refused further therapy None
Unknown
Unknown
Outer third
-
Homologous MMT, endocervix
Unknown
Unknown
Outer third
-
Stromal sarcoma, . endometrium Heterologous MMT, endocervix
Unknown
Unknown
Middle third
-
Unknown
Positive
Middle third
-
Positive
Negative
Serosa
Parametrial involvement
Positive
Negative
Other third
Positive washings
Negative
Negative
Other third
Negative
Negative
Outer third
Tumor type Homologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Homologous MMT, endometrium Homologous MMT, endometrium Homologous MMT
Heterologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium Stromal sarcoma, endocervix
Heterologous MMT, endocervix Homologous MMT, endometrium Heterologous MMT, endometrium Homologous MMT, endometrium
Depth invasion
Treatment deviation
Other Positive washings
Parametrial lymphatic and cervix involvement -
Positive washings
’ MMT, mixed mesodermal tumor; NED, no evidence disease; DOD, dead of disease; d/c, discontinued.
Outcome
None
NED 59 months
None
Died 28 months perforated diverticulum NED 81 months NED 71 months
4 cycles of chemotherapy, then refused further therapy Adriamycin d/c after 2 cycles, cisplatin d/c after 4 cycles None
DOD 23 months
NED 90 months NED 36 months DOD 9 months NED 45 months
5 cycles of chemotherapy, then refused further therapy None
NED 38 months
4 cycles of chemotherapy 2 cycles of chemotherapy, then refused further therapy 6 cycles chemotherapy, no irradiation
NED 34 months
NED 36 months
NED 26 months NED 12 months
326
PETERS ET AL.
surgical findings and subsequent autopsy were more consistent with a perforated diverticulum. This patient had initially presented with extensive pelvic nodal metastasis and her postmortem examination was completely negative for cancer. The other 12 patients are alive and disease free with a median survival of 42 months. Using Kaplan-Meier life-table analysis, there is a 75% projected 5-year survival for group II. Of the seven patients with documented nodal involvement, one patient died with recurrent disease at 23 months, one patient died of 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 alive and disease free more than 5 years after diagnosis. Both patients with documented periaortic nodal metastases are still disease free. Table 3 lists relapses by the number of cycles of chemotherapy patients received in group II. There is a suggestion that survival is diminished with receiving less than four cycles of therapy. There were two relapses in the 11 patients receiving planned irradiation and two relapses in the 6 patients who refused their irradiation.
adjuvant radiation therapy; however, the overall survival rate has not been improved with radiation therapy as patients succumb to systemic disease. Published reports of chemotherapy in patients with metastatic disease have shown a 6-25% response rate with Adriamycin as a single agent [ 12-151. Cisplatin as a single agent had an 18% response rate in heavily pretreated patients [16]. Adriamycin plus DTIC, Adriamycin plus Cytoxan, and VAC have produced similar results [12,15,17-191. In general, responses have been of short duration. Recent reports from Kohorn et al. and Seltzer et al. suggested that the combination of Adriamycin and cisplatin (with or without Cytoxan) was an active combination in patients with metastatic mixed mesodermal tumors [20,21]. A 33% response rate was reported by Grosh et al. to Hexa-CAP [22]. In their patients, cisplatin was given at 60 mg/m’. Piver et al. reported a 20% response rate to DTIC combined with conventional-dose cisplatin and a 50% response rate when cisplatin was given at a dose of 20 mg/m2 daily for 5 days [231. We have had similar experience in treatment of patients with metastatic uterine and ovarian mixed mesodermal tumors and this led to the initiation of a trial of cisplatin and Adriamycin in an adjuvant setting [24,25]. DISCUSSION Most reports with adjuvant chemotherapy have been Endometrial and cervical sarcomas and mixed tumors disappointing. A randomized prospective trial carried out have carried a dire prognosis. A recent review from the by the Gynecologic Oncology Group showed that the University of Michigan showed that in patients with stage single agent, Adriamycin, at a dose of 60 mg/m2, given I and II endometrial tumors, the depth of myometrial every 3 weeks for a total of eight cycles, was not effective invasion was the strongest predictor of survival [2]. in reducing the recurrence rate with endometrial sarThere were no recurrences among patients with disease comas or leiomyosarcomas of the myometrium [26]. Retlimited to the endometrium among patients who had full rospective studies, reported by Hannigan et al. and by surgical staging. Among patients with invasion of the Piver et al., who examined single-agent Adriamycin or outer one-third of the myometrium, the recurrence rate combination therapy with Adriamycin and DTIC, failed approached 100%. When tumor invaded the inner third to show a survival advantage [11,13]. Buchsbaum et al. of the myometrium, survival of 5 years was approxi- and Van Nagell et al. have suggested an improvement mately 75%, and when the tumor invaded the middle in survival with postoperation chemotherapy employing third, survival was approximately 50%. VAC. Their studies are difficult to evaluate because they Experience with adjuvant radiation therapy has been combined patients with mixed mesodermal tumors and extremely discouraging [2,3,6,9,11]. Most studies have patients with leiomyosarcomas and they did not differshown a decrease in the pelvic recurrence rate following entiate between high- and low-risk patients [27,28]. Our data, as well as those of Kohorn et al., would suggest that combined therapy with Adriamycin and cisTABLE 3 platin improves the prognosis of patients with high-risk Recurrences by Number of Cycles of Chemotherapy endometrial and endocervical stromal sarcomas or mixed in Group II mesodermal tumors. Patients with documented positive Relapses/total patients treated Number of cycles nodes were much more likely to continue their chemotherapy and to receive their irradiation, which may ex2 213 plain their excellent survival. There were fewer recur3 4 rences in our patients who received radiation therapy. 013 5 l/3 However, patients who discontinued chemotherapy prior 6 118 to completion of six cycles were much more likely to Total 4117 refuse radiation therapy, making it difficult to evaluate
COMBINATION
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