Outcome of Reproductive Age Women with Stage IA or IC Invasive Epithelial Ovarian Cancer Treated with Fertility-Sparing Therapy

Gynecologic Oncology 87, 1–7 (2002) doi:10.1006/gyno.2002.6805

Outcome of Reproductive Age Women with Stage IA or IC Invasive Epithelial Ovarian Cancer Treated with Fertility-Sparing Therapy Jeanne M. Schilder, M.D., 1,* Amy M. Thompson, M.D., 2 Paul D. DePriest, M.D., 1 Frederick R. Ueland, M.D., 1 Michael L. Cibull, M.D., 3 Richard J. Kryscio, Ph.D., 4 Susan C. Modesitt, M.D., 5 Karen H. Lu, M.D., 5 John P. Geisler, M.D., 6 Robert V. Higgins, M.D., 7 Paul M. Magtibay, M.D., 8 David E. Cohn, M.D., 9 Matthew A. Powell, M.D., 10 Christina Chu, M.D., 11 Frederick B. Stehman, M.D., 12 and John van Nagell, M.D. 1 1

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, 2Department of Obstetrics and Gynecology, 3Department of Pathology, and Department of Biostatistics, University of Kentucky Medical Center, and the Markey Cancer Center, Lexington, Kentucky 40536; 5University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030; 6University of lowa Hospitals and Clinics, lowa City, lowa 52242; 7Carolinas Medical Center, Charlotte, North Carolina 28232; 8Mayo Clinic, Rochester, Minnesota 55905; 9The Ohio State University Medical Center, Columbus, Ohio 43210; 10 Washington University School of Medicine, St. Louis, Minnesota, 63110; 11University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104; and 12Indiana University School of Medicine, Indianapolis, Indiana 46202

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Received March 12, 2002; published online September 6, 2002

97 months after initial treatment. The estimated survival was 98% at 5 years and 93% at 10 years. Twenty-four patients attempted pregnancy and 17 (71%) conceived. These 17 patients had 26 term deliveries (no congenital anomalies noted) and 5 spontaneous abortions. Conclusion. The long-term survival of patients with Stage IA and IC epithelial ovarian cancer treated with unilateral adnexectomy is excellent. Fertility-sparing surgery should be considered as a treatment option in women with Stage I epithelial ovarian cancer who desire further childbearing. © 2002 Elsevier

Objectives. The purpose of this study was to determine the recurrence rate, survival, and pregnancy outcome in patients with Stage IA and Stage IC invasive epithelial ovarian cancer treated with unilateral adnexectomy. Methods. A multi-institutional retrospective investigation was undertaken to identify patients with Stage IA and IC epithelial ovarian cancer who were treated with fertility-sparing surgery. All patients with ovarian tumors of borderline malignancy were excluded. Long-term follow-up was obtained through tumor registries and telephone interviews. The time and sites of tumor recurrence, patient survival, and pregnancy outcomes were recorded for every patient. Results. Fifty two patients with Stage I epithelial ovarian cancer treated from 1965 to 2000 at 8 participating institutions were identified. Forty-two patients had Stage IA disease, and 10 had Stage IC cancers. Cell type was distributed as follows: mucinous, 25; serous, 10; endometrioid, 10; clear cell, 5; and mixed, 2. Histologic differentiation was as follows: grade 1, 38; grade 2, 9; and grade 3, 5. Twenty patients received adjuvant chemotherapy (mean 6 courses, range 3–12 courses). Patients received the following chemotherapeutic agents: cisplatin/taxol or carboplatin/ taxol, 11; melphalan, 5; cisplatin and cyclophosphamide, 3; and single-agent cisplatin, 1. Eight patients had second-look laparotomies and all were negative. Duration of follow-up ranged from 6 to 426 months (median 68 months). Five patients developed tumor recurrence 8 –78 months after initial surgery. Sites of recurrence were as follows: contralateral ovary, 3; peritoneum, 1; and lung, 1. Nine patients underwent subsequent hysterectomy and contralateral oophorectomy for benign disease. At present, 50 patients are alive without evidence of disease and 2 have died of disease 13 and

Science (USA)

INTRODUCTION Ovarian cancer is the fifth leading cause of cancer death in women and the second most common gynecologic cancer in the United States [1]. This year, it is estimated that there will be 23,400 cases of ovarian cancer and that 13,900 women will die of the disease. Although the incidence of epithelial ovarian cancer increases with age, reaching a maximum in the seventh decade of life, it does occur in women of childbearing age as well. Several reports [2– 6] have estimated that 3–17% of all epithelial ovarian cancer occur in women ⬍40 years of age. Likewise, 7– 8% of all malignant Stage I epithelial tumors of the ovary occur in women under 35 years of age [7, 8]. Standard management of epithelial ovarian cancer involves primary surgery including total abdominal hysterectomy and bilateral salpingo-oophorectomy, tumor debulking, omentectomy, pelvic/para-aortic lymph node biopsies, and multiple peritoneal biopsies and washings of the pelvis and abdomen. This is followed by adjuvant chemotherapy, and second-look surgery in selected cases. Many young women with early stage ovarian cancer wish to maintain reproductive capability. Since

* To whom correspondence should be addressed at Indiana University Medical Center, Department of OB/GYN, Division of Gynecologic Oncology, 535 Barnhill Drive, Rm. 436, Indianapolis, IN 46202-6294. Fax: (317) 2744878. E-mail: [email protected]. 1

0090-8258/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.

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SCHILDER ET AL.

the ultimate goal of therapy is to cure the disease, the question becomes, can less than radical surgery preserve fertility without compromising survival? Studies evaluating unilateral oophorectomy in the treatment of patients with ovarian germ cell tumors and borderline epithelial ovarian tumors have reported excellent patient outcome while preserving reproductive and endocrine function [9 –19]. Several authors [20 –22] have suggested that selected patients with early stage invasive epithelial ovarian cancer can be managed successfully with fertilitysparing surgery. However, there are relatively few studies evaluating this approach in large numbers of patients with Stage IA or Stage IC tumors. Also, the current standard regimen of platinum/taxol chemotherapy has yet to be evaluated in a conservatively treated patient population. The present investigation was undertaken in order to evaluate recurrence rate, survival, and reproductive outcome in patients with Stage IA or IC invasive epithelial ovarian cancer treated with fertility-sparing surgery. PATIENTS AND METHODS Subjects for this investigation included all patients with Stage IA and IC epithelial ovarian cancer who were treated with unilateral oophorectomy at one of the eight participating institutions from 1965 to 2000. Patients were eligible if they (1) had histologically confirmed Stage IA or IC grades 1, 2, or 3 epithelial ovarian cancer, (2) were ⬍40 years of age at the time of initial diagnosis, and (3) were surgically staged and treated with conservation of the uterus, one ovary, and fallopian tube. Staging included pelvic/para-aortic lymph node sampling, multiple peritoneal biopsies, washings, and subtotal omentectomy. Institutional Review Board (IRB) approval was obtained from each institution, and all patients or their families were required to provide informed consent prior to entry into this study. None of the eligible patients refused to participate. Patients with borderline epithelial ovarian tumors, ovarian germ cell tumors, or ovarian stromal tumors were excluded from this investigation. Likewise, patients who had received prior abdominal or pelvic radiotherapy were ineligible for study. Pathology slides were reviewed by one pathologist from each institution to confirm cell type, histologic differentiation, and stage of disease. Tumors were classified histologically according to the World Health Organization (WHO) System and were staged according to the International Federation of Gynecology and Obstetrics (FIGO) System. Central pathology review was performed at the University of Kentucky in cases in which there was a question concerning tumor cell type or histologic differentiation. Hospital records, office records, and institutional and/or state registries were used as sources for patient data. Telephone interviews with patients and their family members were conducted to supplement data from the hospital records, specifically in regard to patient survival and reproductive outcome.

TABLE 1 Patient Demographics and Tumor Characteristics in Cases Studied (N ⴝ 52)

Age (years) Gravidity Race Caucasian Hispanic Indian Asian African-American Stage IA IC Cell Type Mucinous Serous Endometrioid Clear cell Mixed Histologic differentiation Well (G1) Moderate (G2) Poor (G3)

Mean

Range

26 0.4

(11–40) (0–7)

44 (84%) 4 (8%) 2 (4%) 1 (2%) 1 (2%) 42 (81%) 10 (19%) 25 (48%) 10 (19%) 10 (19%) 5 (10%) 2 (4%) 38 (73%) 9 (17%) 5 (10%)

Finally, state and social security mortality records were reviewed for each patient in the study. Statistical analysis of the data was performed using univariate and multivariate analyses. Proportions were compared using the ␹ 2 statistic from the corresponding contingency tables. Statistical significance was determined at the 0.05 level. Survival estimates were generated using the Kaplan-Meier method. RESULTS Fifty-two patients with Stage I epithelial ovarian cancer treated with unilateral oophorectomy and who met the eligibility criteria were identified. Clinical and histologic characteristics of the patients studied are illustrated in Table 1. Forty-two patients had Stage IA disease and 10 had Stage IC cancers. Patients were included in Stage IC on the basis of positive peritoneal washings or ascites. The mean age of the patients was 26 years (range 11– 40 years) and the mean gravidity was 0.4 (range 0 –7). Tumor cell types were as follows: mucinous, 25; serous, 10; endometrioid, 10; clear cell, 5; and mixed, 2. Histologic differentiation of the tumors studied was as follows: well differentiated (G1), 38; moderately differentiated (G2), 9, and poorly differentiated (G3), 5. Adjuvant chemotherapy (Table 2) was given to 11 patients with Stage IA ovarian cancer (26%) and 8 patients with Stage IC disease (80%). The most common chemotherapy regimens were either cisplatin/taxol or carboplatin/taxol (53%) and oral melphalan (26%). The mean number of chemotherapy courses

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FERTILITY-SPARING SURGERY FOR EARLY STAGE OVARIAN CANCER

TABLE 2 Adjuvant Chemotherapy According to Tumor Substage and Grade Tumor substage and grade

N

No ChemoRx

Platinum/ Taxol

Platinum/ cyclophosphamide

cisplatin alone

Melphalan

IA1 IA2 IA3 IC1 IC2 IC3 Total

33 6 3 5 3 2 52

27 4 0 2 0 0 33

1 1 3 1 2 2 10

1 1 0 1 0 0 3

0 0 0 1 0 0 1

4 0 0 0 1 0 5

was 6 (range 3–12). Eight patients (Stage IA– 6, Stage IC–2) underwent second-look surgery, and all were negative for residual disease. Five patients developed tumor recurrence 8 –78 months following initial surgery (Table 3). Four of these patients had Stage IA cancers and one had Stage IC disease. Three patients experienced recurrence to the contralateral ovary in the pelvis 8, 13, and 69 months after initial surgery. Two were treated by surgery alone and one by surgery with chemotherapy. All three of these patients are alive and well with no evidence of disease 10 – 43 months (mean 21 months) after diagnosis of recurrence. There were two deaths in this series. One patient with a Stage IA grade 1 mucinous ovarian carcinoma developed regional recurrence to the abdominal peritoneum 9 months after unilateral adnexectomy, and was treated with carboplatin/taxol chemotherapy. Her tumor did not respond to chemotherapy, and she died of intraperitoneal carcinomatosis 4 months after the diagnosis of recurrence. The second patient had a Stage IA grade 2 mucinous ovarian carcinoma and developed a pulmonary metastasis 78 months following initial therapy. This le-

sion was biopsied and was identical histologically to her primary ovarian cancer. She was treated with chemoradiation, but died of disease 19 months after the diagnosis of recurrence. The relationship of tumor substage, cell type, and histologic differentiation to the frequency of recurrence is presented in Table 4. There was no statistically significant relationship between substage or tumor histology and the frequency of tumor recurrence. Three of the 14 patients with grade 2 or 3 disease recurred. Four of the remaining 11 patients underwent completion surgery, and 7 did not. Two patients were diagnosed with metachronous gynecologic malignancies during the period of follow-up. One patient developed a Stage IB grade 2 adenosquamous carcinoma of the endometrium 52 months after unilateral salpingo-oophorectomy and 12 courses of alkeran chemotherapy for a Stage IC grade 2 endometrioid carcinoma of the ovary. She was treated with total abdominal hysterectomy, contralateral salpingooophorectomy, and external pelvic radiation, and is currently alive with no evidence of disease 12 years after the diagnosis of endometrial cancer. The second patient developed a cystic

TABLE 3 Clinical Characteristics and Treatment of Patients with Tumor Recurrence Cell type

Primary Rx

Site recurrence

Time to recurrence

Salvage Rx

Contralateral ovary Peritoneal carcinomatosis Contralateral ovary

69 months

TAH/LSO

9 months

Debulking

LSO

Lung

78 months

LSO ChemoRx (C/T ⫻ 3)

Contralateral ovary

Patient

Age

Substage

Grade

HW

32

IA

1

Ser

RSO

LR

30

IA

1

Muc

RSO

JD

32

IA

2

End

LSO

AD

19

IA

2

Muc

PD

34

IC

2

Ser/End

13 months

8 months

TAH/BSO ChemoRx (C/T ⫻ 6) Radiation ChemoRx (C/T ⫻ 3) TAH/RSO ChemoRx (C/T ⫻ 3)

Status NED 83 months DOD 13 months NED 53 months DOD 97 months NED 18 months

Note. Ser, serous; Muc, mucinous; End, endometrioid; LSO, left salpingo-ooporectomy; RSO, right salpingo-oophorectomy; NED, no evidence of disease; DOD, dead of disease.

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SCHILDER ET AL.

TABLE 4 Recurrence Related to Tumor Substage, Cell Type, and Histologic Differentiation (N ⴝ 52) Stage

N

Recurrence

Status

IA

42

4 (9.5%)

40 NED 2 DOD

IC Cell type Mucinous

10

1 (10%)

10 NED

25

2 (8%)

Serous Endometrioid Clear cell Mixed Histologic differentiation Grade 1

10 10 5 2

1 (10%) 1 (10%) 0 (0%) 1 (50%)

23 NED 2 DOD 10 NED 10 NED 5 NED 2 NED

38

2 (5.2%)

Grade 2

9

3 (33%)

Grade 3

5

0 (0%)

Significance

NS

NS

37 NED 1 DOD 8 NED 1 DOD 5 NED

NS

Note. NED, no evidence of disease; DOD, dead of disease; NS, Nonsignificant.

tumor of borderline malignancy of the left ovary 26 months following right salpingo-oophorectomy for a Stage IA grade 2 serous carcinoma of the ovary. Histologic review of the left ovarian tumor revealed a distinctly different histologic pattern from the primary invasive ovarian carcinoma. Therefore, she was thought to have a second primary ovarian tumor of low malignant potential. She was treated with right salpingooophorectomy alone since she wished to participate in artificial reproductive techniques. She is alive and well with no evidence of disease 43 months after treatment. Eight patients underwent hysterectomy with contralateral oophorectomy for benign indications during the period of follow-up. At present, 50 patients are alive without evidence of recurrence 6 – 423 months (median 68 months) after initial treatment. Two patients have died of disease 13 and 97 months after diagnosis. The estimated survival of these patients is 98% at 5 years and 93% at 10 years. Following treatment, 24 patients (Stage IA–22, Stage IC–2) attempted pregnancy and 17 (71%) conceived (Table 5). Six of these 17 patients had received prior chemotherapy (platin/ taxol, 3; platin/cyclophosphamide, 2; alkeran, 1). These patients had 26 term pregnancies and 5 spontaneous abortions. There were no congenital anomalies reported in any of the offspring.

A summary of the reported cases of Stage I epithelial ovarian cancer treated by unilateral oophorectomy [23–26] is presented in Table 6. Although 5 and 10 year survivals were not reported in some of these studies, 135 out of 144 patients (94%) are alive with no evidence of disease at a median of 70 months after therapy. Forty-six women treated with fertilitysparing surgery became pregnant and delivered 54 term pregnancies. There were no congenital anomalies reported in any of these pregnancies. DISCUSSION During the past two decades, there has been a trend toward less radical surgery in patients with early stage breast cancer, cervical cancer, vulvar cancer, and ovarian germ cell malignancies [27–31]. Benefits of this therapeutic approach include reduced operative morbidity and mortality, enhanced patient self-image, and in the case of ovarian cancer, retention of reproductive function. Early detection methods, improved patient selection based on clinico-pathologic variables, and more effective adjuvant therapies have allowed the use of conservative surgery while maintaining or improving patient survival. Findings of the present investigation indicate that selected patients with Stage I epithelial ovarian cancer who desire

TABLE 5 Reproductive Outcome of Patients Studied Attempting pregnancy

Achieved pregnancy

Term pregnancy

Current pregnancy

Spontaneous abortion

Congenital anomalies

24

17

26

1

5

0

5

FERTILITY-SPARING SURGERY FOR EARLY STAGE OVARIAN CANCER

TABLE 6 Fertility-Sparing Surgery in Patients with Stage I Epithelial Ovarian Cancer Median Follow-up (months)

Reproductive outcome

Author

Substage

N

Recurrence

Site

Survival

Zanetta et al. (1997)

IA

36

4

Brain, 1 Contralateral ovary, 1 Lung, 1 Spleen, 1

53 NED 3 DOD

94 (34–175)

IB

1

0

20 patients 27 conceptions 17 term deliveries 8 abortions 2 ectopics 0 congenital anomalies

IC IA

19 12

1 2

14 NED 2 DOD

66 (1–174)

IC

4

0

5 8 8 0

patients conceptions term deliveries congenital anomalies

IA

19

3

18 NED

47 (6–201)

IC

1

1

4 4 3 1 0

patients conceptions term deliveries abortion congenital anomalies

IA

42

4

78 (3–423)

IC

10

17 patients 32 conceptions 26 term deliveries 5 abortions 1 current pregnancy 0 congenital anomalies

Brown et al. (2000)

Morice et al. (2001)

Schilder et al. (2002)

Contralateral ovary Contralateral ovary

Contralateral ovary, 3

2 DOD

Contralateral ovary, 3 Lung, 1 Peritoneum, 1

further childbearing can be treated safely with unilateral oophorectomy. It is important to emphasize that patients selected for conservative surgery should have complete surgical staging. Several authors [32–35] have reported lymph node metastases in patients with clinically apparent Stage I ovarian cancer. Cass and colleagues [35], for example, noted that 14 of 96 women (15%) with apparent Stage I epithelial ovarian cancer at the time of surgery had occult lymph nodal metastases. Three patients had isolated metastatic involvement of contralateral pelvic/para-aortic lymph nodes. Therefore, proper staging should include both ipsilateral and contralateral pelvic/ para-aortic lymph node sampling, as well as partial omentectomy with multiple biopsies and washings of the pelvis and abdomen. Also, it should be noted that a small number of women with presumed Stage I endometrioid ovarian carcinoma may have a coexisting endometrioid cancer of the endometrium. Kottmeier and colleagues [36], for example, reported that as high as 14% of patients with endometrioid ovarian cancer had endometrioid carcinoma of the endometrium as well. For this reason, it is recommended that uterine curettage be included in the staging of Stage I epithelial ovarian cancers, particularly those of endometrioid cell type. The indications for adjuvant chemotherapy in patients with Stage I epithelial ovarian cancer treated with unilateral salpingo-oophorectomy should be based on tumor substage, cell type, and histologic differentiation. A number of studies [37– 39] have concluded that the use of adjuvant chemotherapy

50 NED 2 DOD

offers no survival advantage to patients with well-differentiated Stage IA epithelial ovarian cancers. Twenty-seven of the 33 patients with Stage IA grade 1 cancers in the present series received no chemotherapy. Two of these patients recurred and one died of disease. In contrast, most recent studies [37– 40] report that the use of adjuvant chemotherapy improves in the survival of patients with moderately or poorly differentiated Stage I epithelial ovarian cancer. Five of 9 patients with Stage IA (G2) or IA (G3) tumors and 5 of 5 patients with Stage IC (G2) or Stage IC (G3) tumors received adjuvant chemotherapy in this study. One of these patients developed tumor recurrence in the contralateral ovary 8 months after therapy and is now alive without evidence of disease 10 months after hysterectomy with contralateral oophorectomy and additional chemotherapy. Several recent studies [41– 43] indicate that patients with Stage I clear cell cancer of the ovary have a poor prognosis and should be treated with adjuvant chemotherapy. All of the 5 patients with clear cell carcinoma in the present series received adjuvant platinum/taxol chemotherapy, and all are alive and well without evidence of recurrence. At present, there is little evidence to suggest that there are different indications for chemotherapy in Stage I ovarian cancer patients treated with conservative surgery when compared to similar patients treated with more radical surgery [23, 24]. The value of second-look surgery in patients with Stage I ovarian cancer treated initially with unilateral salpingo-oophorectomy and chemotherapy cannot be assessed from this study.

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SCHILDER ET AL.

Only 8 patients underwent second-look laparotomies and all were negative. It should be noted that 2 of the 3 patients who developed pelvic recurrence did so within 1 year of treatment and both had masses in the contralateral ovary detected on ultrasound. Therefore, all patients treated with conservative surgery for Stage I ovarian cancer should be followed every 3 months with serum Ca-125 determinations and transvaginal sonography for a minimum of 2 years whether or not they undergo second-look surgery. The question of whether hysterectomy and contralateral adnexectomy should be undertaken following completion of childbearing remains to be answered. This is an attractive option to some patients, given the potential for a second primary or recurrent ovarian cancer in a patient already proven to be at risk. However, the salvage rate of patients who recurred, and the long-term disease-free survival in those patients who did not undergo completion surgery, suggests that expectant management is a viable option as well. The young age at diagnosis places these patients in a higher risk group, and genetic testing can be offered in order to more clearly define individual risk. Data from the present investigation indicates that successful reproduction in patients with Stage I ovarian cancer treated by conservative surgery with or without chemotherapy is not only possible but probable. Seventeen of 24 patients (71%) attempting pregnancy conceived, and had 26 term deliveries and only 5 spontaneous abortions. There were no congenital anomalies noted in the offspring of these pregnancies or in the 28 additional term pregnancies reported in the literature (Table 6). This confirms the results of previous investigations [44 – 47] which have documented successful reproductive function following chemotherapy for Hodgkin’s disease, and germ cell malignancies of the ovary. Gershenson and colleagues [45], for example, reported that 11 of 15 patients attempting pregnancy conceived after combination VAC chemotherapy for germ cell ovarian tumors. These 11 patients delivered 22 healthy infants. Perhaps the most important finding of the present investigation is that patients with Stage I epithelial ovarian cancer treated with fertility-sparing surgery have an excellent prognosis. The estimated 5-year and 10-year survivals of patients in this series was 98 and 93%, respectively, which compares favorably to the reported survival rates of patients with Stage I ovarian cancer treated by more radical surgery [48 –51]. This is retrospective data, however, and points out the need for the establishment of a national registry in which Stage I ovarian cancer patients who are treated with conservative surgery can be enrolled prospectively. Nevertheless, the results of this and other recent studies [24 –26] indicate that young women with Stage I epithelial ovarian cancer need not sacrifice fertility in order to receive successful treatment of their disease.

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