Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination

Transcription

1 FERTILITY AND STERILITY VOL. 74, NO. 4, OCTOBER 2000 Copyright 2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination Philippe Morice, M.D., Laurent Juncker, M.D., Annie Rey, Janah El-Hassan, M.D., Christine Haie-Meder, M.D., and Damienne Castaigne, M.D. Institut Gustave Roussy, Villejuif, France Objective: To assess the indications, effectiveness, and complications of ovarian transposition before pelvic irradiation for cervical cancer. Design: Prospective study. Setting: Gynecologic oncology department at a French cancer center. Patient(s): One hundred seven patients treated for cervical cancer. Intervention(s): Ovarian transposition to the paracolic gutters with radical hysterectomy and lymphadenectomy. Main Outcome Measure(s): Clinical and laboratory follow-up tests for ovarian function. Result(s): Bilateral ovarian transposition was achieved in 104 patients (98%). Twelve patients were lost to follow-up or excluded because of evolution of the disease. Preservation of ovarian function was achieved in 83% of the patients having follow-up. The rates of ovarian preservation were 100% for patients treated exclusively by surgery, 90% for patients treated by postoperative vaginal brachytherapy, and 60% for patients treated by postoperative external radiation therapy and vaginal brachytherapy. The main risk for ovarian failure was found in patients treated by external radiation therapy. Conclusion(s): Ovarian transposition is a safe and effective procedure for preserving ovarian function in patients treated by a radiosurgical combination. This procedure should be performed in patients 40 years of age with a small invasive cervical carcinoma ( 3 cm) treated by initial surgery. In such selected cases, the risk of ovarian metastasis is low. (Fertil Steril 2000;74: by American Society for Reproductive Medicine.) Key Words: Ovarian transposition, function preservation, cervical cancer, brachytherapy, external radiation therapy Received January 24, 2000; revised and accepted April 13, Reprint requests: Philippe Morice, M.D., Service de Chirurgie Gynécologique, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif Cedex, France (FAX: ) /00/$20.00 PII S (00) Ovarian transposition was described by McCall et al. (1) in 1958 for patients treated for cervical carcinoma. Recently, Levitt and Jenney (2) published a literature analysis about the effect of anticancer treatment on the reproductive system. These investigators concluded that ovarian transposition is a poor-effectiveness procedure (2). In our institution, ovarian transposition has been performed for the last 15 years for patients 40 years of age treated for an earlystage cervical carcinoma by a radiosurgical combination. The aims of this large study were to assess the functional outcome and complication rate after ovarian transposition followed by radiation therapy and to discuss indications for this surgical procedure in patients treated for an invasive cervical carcinoma. MATERIALS AND METHODS Patients From May 1985 to March 1998, 107 patients at the Institut Gustave Roussy underwent ovarian transposition during surgical treatment of cervical cancer (radical hysterectomy with lymphadenectomy). We did not request institutional review board approval for this study because it was not randomized. Furthermore, this study evaluated a surgical procedure that has been routine in our institution since 1970 for others cancers (Hodgkin disease, pelvic sarcoma, ovarian dysgerminoma). Procedures were performed after obtaining patients oral permission. 743

2 FIGURE 1 Position of the right ovary (A) and left ovary (B) identified with two metallic clips. Morice. Ovarian transposition in cervical carcinoma. Fertil Steril Surgical Procedure Radical hysterectomy and ovarian transposition were performed by laparotomy in 102 patients and by laparoscopy in 5 patients. For patients treated by laparotomy, the surgical procedure consisted of a radical hysterectomy with ovarian preservation through a midline incision, with resection of the lower part of the parametria (class III according to the classification of Piver et al.) (3). A pelvic lymphadenectomy with frozen-section analysis of the pelvic lymph nodes was performed for patients with a tumor size of 2 cm (4). A pelvic and paraaortic lymphadenectomy was performed systematically for patients with a tumor size of 2 cm and/or for patients with a small tumor but with lymph node involvement found during frozen-section analysis (5). Ovarian transposition was performed when the ovaries looked macroscopically normal, and they were both transposed according to a technique described previously (6). First, the ovaries were mobilized and grasped. The ureters were identified through the peritoneum. The uteroovarian ligament was cut off at its uterine origin, and the fallopian tubes were separated from the ovaries through the mesovarium. The peritoneum was then incised along the infundibulopelvic ligament to mobilize the ovaries completely. Dissection of the ovarian vessels was performed up to the level of the aortic bifurcation. The ovaries were transposed bilaterally to the paracolic gutters. The ovarian vessels were not tunneled retroperitoneally. The left ovary was fixed at the level of the aortic bifurcation and the right ovary was fixed above the pelvic brim, between the level of the aortic bifurcation and the lower pole of the right kidney. Two metallic clips were applied to each transposed ovary to be identified by subsequent x-ray localization (Fig. 1). For patients treated by laparoscopy, pneumoperitoneum was achieved and a 10-mm trocar was inserted just below the umbilicus. Two suprapubic 5-mm trocars were placed laterally, and a 10-mm trocar was introduced medially to retrieve the lymph nodes. The operative procedure began with complete surgical staging and careful inspection of the ovaries, peritoneum, and the whole abdominopelvic cavity. Peritoneal fluid sampling and peritoneal washing were performed. Then a pelvic lymphadenectomy and laparoscopy-assisted radical vaginal hysterectomy were performed according to the procedure described by Dargent and Mathevet (7). The surgical procedure of laparoscopic ovarian transposition was identical to the one performed by laparotomy (8). At the end 744 Morice et al. Ovarian transposition in cervical cancer Vol. 74, No. 4, October 2000

3 of the ovarian transposition, the ovaries were fixed with two transaponeurotic sutures. Postoperative Treatment Postoperative treatment was administered according to the tumor size, the histologic results (potential presence and topography of lymphovascular space involvement; nodal status), and local invasion. The patients were divided into three groups according to the postoperative treatment administered. Patients with a small tumor ( 1 cm) and with no evidence of invasion of the surgical margins, without lymphovascular space involvement, and free of lymph node metastasis received no postoperative treatment. These patients were treated exclusively by surgery (group 1). Patients with a tumor of 1 cm in diameter (with or without cervical lymphovascular space involvement) and free of lymph node metastasis received vaginal brachytherapy alone (60 Gy) (group 2). Patients with metastatic lymph nodes and/or with parametrial lymphovascular space involvement received external pelvic irradiation (45 Gy) boosted by uterovaginal brachytherapy (15 Gy) (group 3). The daily fraction for patients who received external irradiation was 1.8 Gy. Adjuvant cisplatin-based chemotherapy was delivered with external radiation therapy for patients with common iliac and/or paraaortic node involvement. Doses reaching the ovaries were calculated according to procedures described previously (9). Evaluation of Ovarian Function Ovarian function was assessed by a routine postoperative ultrasound (US) scan and measurement of gonadotropin and E 2 levels 6 months after the transposition and then yearly afterward. This assessment was repeated at shorter intervals when hot flushes or menopausal symptoms were reported. Ovarian function was considered normally preserved when the FSH level was 10 miu/ml, E 2 was 50 pg/ml, and when follicles were present on the US scan. When patients complained of abdominopelvic pain, US was performed to rule out a causative ovarian pathology. Statistical Analysis The Student s t-test was used to compare means. The 2 test was used to compare percentages, and P.05 was considered statistically significant. RESULTS The median age of the patients was 33 years (range, years). Details concerning the tumor type, tumor size, nodal status, and stage of the disease (according to the International Federation of Gynecology and Obstetrics staging system) (10) are presented in Table 1. Bilateral ovarian transposition was achieved in 104 patients and unilateral TABLE 1 Clinical and histologic characteristics of patients during follow-up. Variable Group 1 Group 2 Group 3 Total Mean age (y) a 33 (25 39) 34 (26 42) 32 (21 39) 33 (21 42) Age (y) Tumor stage (FIGO) IB IB IIA Tumor size (cm) ; Histology Adenocarcinoma Squamous cell carcinoma Nodal status N N pelvic nodes N paraaortic nodes Total Note: Group 1 exclusive surgery; group 2 surgery brachytherapy; group 3 surgery external radiation therapy brachytherapy. FIGO International Federation of Gynecology and Obstetrics. a Mean (range). Morice. Ovarian transposition in cervical carcinoma. Fertil Steril transposition in 3 patients (1 patient with a history of adnexectomy and 2 patients with contralateral benign cysts). No intraoperative or immediate postoperative morbidity related to the ovarian transposition procedure was observed. Twelve patients were excluded from the evaluation of ovarian function: 4 patients were lost to follow-up and 8 patients could not have their climacteric functions well evaluated; of those, 6 had rapid deterioration due to early recurrence of the tumor and 2 had major bowel complications (chronic enteritis related to radiation therapy). Eventually, 95 patients were followed up and their ovarian function was analyzed. The median ( SD) duration of follow-up was months (range, months). Postoperative Treatments Eleven patients did not receive postoperative irradiation (group 1). Fifty-nine patients received vaginal brachytherapy (group 2). Twenty-five patients received external radiation therapy with vaginal brachytherapy (group 3). Adjuvant chemotherapy was performed in this last group in 7 patients: 5 patients received bleomycin-ameticyn-cisplatin-etoposide and 2 patients received cisplatin plus 5-fluorouracil. The dose of cisplatin was 100 mg/m 2. FERTILITY & STERILITY 745

4 TABLE 2 Results of ovarian transposition. Variable Group 1 Group 2 Group 3 P value Mean dose/ovary (Gy) a ( ) 5.2 ( ).001 Median dose/ovary (Gy) a ( ) 2.8 ( ) Ovarian cysts b 2 (18) 20 (34) 0.05 Menopause b 0 6 (10) 10 (40).01 Rate of menopause according to age at treatment (y) (10) 6 (40) NS (11) 4 (40) Total in group Note: For groups, see Table 1. NS not significant. Range is given in parenthesis. b Values are in (%). Morice. Ovarian transposition in cervical carcinoma. Fertil Steril Ovarian Function Ovarian function was preserved in 83% of the patients (79/95). The rates of preservation of ovarian function according to the type of treatment were as follows: 100% (11/11) in group 1, 90% (53/59) in group 2, and 60% (15/25) in group 3 (P.001; ). Details concerning the radiation dose affecting the transposed ovaries and ovarian function are presented in Tables 1 and 2. Sixteen patients had menopause during treatment of the initial tumor. Nine patients (10%) experienced menopause promptly at the end of the treatment ( 18 months). Seven young patients (22 32 years) (7%) presented with climacteric symptoms slightly delayed from the end of the treatment (median delay, 48 months; range, months). These 7 patients were considered as having treatment-induced menopause from a delayed effect of the radiation. Eleven patients had their menopause at a physiologic age ( 45 years) and remote from cessation of the treatment ( 5 years). These 11 patients were considered as having a physiologic menopause that was not related to the mode of treatment of their cancer. Complications of Ovarian Transposition Twenty-seven delayed complications were observed. One patient with a bulky squamous cell carcinoma presented with an ovarian metastasis and died from recurrence of the disease (11). This 34-year-old patient had a stage Ib cervical tumor without nodal involvement but with involvement of the cervical lymphovascular space and invasion of the uterine isthmus. There was no lymphovascular space involvement in the parametria, and the surgical margins were free of tumor. Therefore, postoperative brachytherapy was delivered, but the patient presented with ovarian metastasis 3 years after completion of the treatment (11). Benign ovarian cysts were observed in 22 patients (23%). These cysts were diagnosed on US, performed routinely in any reported case of abdominal pain. Nineteen patients were treated successfully by oral contraceptive pills. The 3 other patients needed surgical intervention (by laparoscopy in 1 case) for persistent cysts (luteal cyst in 1; mucinous and serous benign cysts in the remaining 2 patients). The rates of ovarian cysts were 18% (2/11) in group 1, 34% (20/59) in group 2, and 0% (0/29) in group 3 (P.01; 2 8.1). Three patients had chronic abdominal pain at the site of the transposed ovaries, without any evidence of a cyst on radiologic examination. One patient was surgically treated for a mechanical bowel obstruction due to the formation of a band of adhesions between the omentum and the transposed right ovary. DISCUSSION The rationale behind ovarian transposition before radiotherapy is to maintain ovarian function. In the literature, several series have studied the role and efficacy of this surgical procedure in maintaining ovarian function (12 15). In those series, however, most of the patients were treated by radical surgery alone, and only a limited number of them received radiation therapy (21% in the series of Feeney et al. (12) and 29% in the series of Anderson et al. (13)). The sample sizes of patients with cervical carcinoma treated by surgery with ovarian transposition and with radiation therapy involve samples of 8 28 patients (12 18). In our series, 84 irradiated patients with invasive cervical carcinoma had ovarian transposition and were followed up and studied. So far, this series involves the largest number of patients with transposed ovaries treated by postoperative radiation therapy (brachytherapy with or without external radiation therapy). For the last 15 years, the mainstay of treatment of patients with stages Ib and II cervical carcinoma at our center has been a radiosurgical combination, with good results for survival and an acceptable rate of complications (5, 19). Starting in 1995, only a small number of patients (patients with tumor of 1 cm, without nodal involvement, and with 746 Morice et al. Ovarian transposition in cervical cancer Vol. 74, No. 4, October 2000

5 a disease-free lymphovascular space) did not receive postoperative radiation therapy. These strict selection criteria justify our percentage of patients treated by adjuvant radiation therapy. With our strategy, radiation therapy is administered according to the initial tumor size, the histologic findings of the tumor, and the lymph nodes status. These histologic prognostic factors cannot be defined accurately before a complete assessment of the specimens removed during the surgical procedure. This point explains why it is impossible to decide clearly and safely which patients will not require postoperative radiation therapy and, hence, no ovarian transposition, before the surgical procedure. In the literature, the rate of ovarian failure after radiation therapy varies from 12% to 66% (13, 14). In these series, however, the difference in results between brachytherapy and external radiation therapy is not clearly defined, probably because the results of those patients were not interpreted separately, as in groups 2 and 3, respectively, in our series. In our series, 62% of the patients with follow-up received vaginal brachytherapy, and 26% had external radiation therapy in addition to vaginal brachytherapy. The rates of ovarian failure were 10% and 40%, respectively (Table 2). In our series, the rate of preservation of ovarian function was very good after brachytherapy and relatively good after external radiation therapy. With regard to the conclusion of Anderson et al. (13) that ovarian transposition is not justified in patients in whom radiation therapy is likely to be needed, we believe that when young patients are scheduled to receive postoperative radiation therapy, we should not spare any effort in performing ovarian transposition to preserve an important part of their endocrine function. On the other hand, should we propose the option of ovarian transposition to all young patients with cervical cancer? The carcinogenic risk of ovarian transposition involves the incidence of ovarian metastasis after ovarian transposition. In our center, at the beginning of our experience, primary surgery was performed in young patients ( 40 years) with stages Ib or IIa cervical cancer to preserve ovarian function by transposing the ovaries. This point explains why, at the time of this series, we had performed ovarian transposition for few patients with stage II or with a tumor size of 4 cm. Some of these patients died rapidly from recurrence of the disease. However, in 1988, we observed one case of ovarian metastasis (11). When we reviewed our case on the basis of reports in the literature, we noticed that among patients who had a bulky tumor, the risk of ovarian metastasis was increased in transposed ovaries (20, 21). In the series of Sutton et al. and Tabata et al., most of the patients treated for a stage Ib or II cervical cancer with ovarian metastasis had a tumor with extracervical disease (21) and/or uterine corpus invasion (20). In the case of the ovarian metastasis in our series, the patient had no positive lymph nodes but had evidence of uterine corpus invasion and lymphovascular space involvement. After this case, we recommended that ovarian conservation and transposition are to be performed only in young patients with small tumors ( 3 cm; stage Ib1 according to the International Federation of Gynecology and Obstetrics classification) (10). Another risk factor for ovarian metastasis discussed in the literature is the histologic type of the tumor. Tabata et al. (20) found a high rate of ovarian metastasis in patients treated for stages Ib to III cervical adenocarcinoma, compared with patients treated for squamous cell carcinoma (28% versus 17% 20%). On the other hand, in the study by Sutton et al. (21) for the Gynecologic Oncology Group, the rate of ovarian metastasis did not correlate significantly with the histologic type of the tumor. In our case of ovarian metastasis, the patient was treated for a squamous cell carcinoma. In a recent study, Natsume et al. (22) concluded that ovarian transposition is a reasonable option for patients with adenocarcinoma macroscopically confined to the uterine cervix, but they recommended that one perform an intraoperative inspection of the radical-hysterectomy specimen to identify deep cervical invasion and/or extrauterine spread. If these findings are positive, ovarian conservation should be abandoned (22). We agree with Owens et al. (14) that ovarian preservation and transposition can be performed in patients with early-stage disease and macroscopically normal ovaries regardless of the histologic type. The other complication after ovarian transposition is the occurrence of ovarian cysts. In their series, Feeney et al. (12) observed only 3% of ovarian cysts requiring surgery or analgesics. Our rate of cysts was greater because we included in our evaluation those patients with cysts diagnosed during US that required exclusively hormonal therapy for management. The rate of benign ovarian cysts that we observed is similar to that observed by Chambers et al. (15) (24%). As did Chambers et al. (15), we observed a lower incidence of cyst formation in patients treated by external radiation therapy, which explains in part the higher rate of menopausal patients observed in this group of the study. In the study by Chambers et al. (15), 4 of 6 patients with ovarian cysts underwent a surgical procedure, but only 3 of 22 patients (14%) required surgery in our study. In most of the cases, these cysts were successfully treated by hormonal therapy. Surgery is indicated only in cases of persistent cysts, complicated cysts, and/or suspicious cysts during radiologic examinations. In cases of persistent benign cysts, some investigators successfully used a GnRH agonist (23). Radioguided percutaneous puncture also could be proposed in such cases to avoid surgery. Until what age should ovarian transposition be per- FERTILITY & STERILITY 747

6 formed? After 40 years of age, the rate of menopause after hysterectomy is obviously too high to recommend ovarian preservation and transposition to patients treated for cervical cancer (24). Hence, such a procedure should be proposed only for patients aged 40 years. In the series of Haie- Meder et al. (9), two factors influenced the rate of preservation of ovarian function after ovarian transposition, namely the dose given to the ovaries (depending on the type of radiation therapy delivered, brachytherapy or external radiation therapy) and the age of the patients. The age of 25 years appeared to be indicative of an eventual ovarian castration, so the cutoff age in the series of Haie-Meder et al. (9) was 25 years. However, in that study, most of the patients were treated for tumors that occurred at a younger age (Hodgkin disease, ovarian dysgerminoma) (9). In our series, age was not a prognostic factor for ovarian failure because the cutoff age of patients was 35 years old. Between 35 and 40 years old, the rate of ovarian preservation appears to be good (Table 2). Moreover, the number of patients aged 25 years in our series was not sufficient to establish an adequate statistical analysis using this cutoff value for age. In conclusion, ovarian transposition is a safe and effective procedure for the preservation of ovarian function in patients 40 years old treated for cervical cancer by a radiosurgical combination. To minimize the risk of ovarian metastasis, such a procedure should be performed regardless of the histologic type in patients with an early invasive cervical cancer, with a tumor size of 3 cm, with tumor confined to the uterine cervix, and with absent macroscopic extrauterine spread. References 1. McCall ML, Keaty EC, Thompson JD. Conservation of ovarian tissue in the treatment of the carcinoma of the cervix with radical surgery. Am J Obstet Gynecol 1958;75: Levitt GA, Jenney MEM. The reproductive system after childhood cancer. 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