Cristina Sigismondi

Is adjuvant chemotherapy indicated in stage I pure immature ovarian teratoma (IT)? A multicentre Italian trial in ovarian cancer (MITO-9).

OBJECTIVE Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for stage I immature ovarian teratoma (IT), except for stage IA G1. Nevertheless the use of chemotherapy in stage IA G2-3 and IB-IC is controversial. The aim of this study was to evaluate the outcome of patients with IT in order to define the role of chemotherapy in stage I disease. METHODS Twenty-eight patients with stage I IT treated in MITO centers were retrospectively reviewed. Grade, stage, age, surgical and postoperative treatment were analyzed using χ(2) test and T test looking for association with recurrence. RESULTS Median age was 25.5. Twenty-four patients underwent fertility-sparing surgery. FIGO stages were 19 IA, 2 IB, and 7 IC. Nine patients had grade 1 tumor, 12 grade 2, and 7 grade 3. Nine patients received adjuvant chemotherapy. Overall recurrence rate was 21.4% (2 in chemotherapy group and 4 in the group without treatment). No patients with G1 had recurrence, whereas 25% of G2 and 42.9% of G3 relapsed. Recurrence rate was not significantly different according to stage, grade or adjuvant chemotherapy, whereas it was greater in the group not operated in a MITO center, not staged and of age lower than 20 years, with statistical significance. At recurrence 4 patients presenting with mature teratoma were treated with surgery alone, whereas 2 recurring with IT were treated with surgery plus chemotherapy. After a median follow-up of 59 months all patients are NED. CONCLUSIONS Our study suggests that chemotherapy may be withheld for primary therapy and utilized only for recurrence.

Outcome and risk factors for recurrence in malignant ovarian germ cell tumors: a MITO-9 retrospective study.

Aims: This study aimed to investigate the outcome of patients with malignant ovarian germ cell tumors (MOGCTs) and to define the risk factors for recurrence. Methods: A total of 123 patients with MOGCTs were retrospectively reviewed among MITO centers. Eighty-one patients had primary treatment in a MITO center, whereas the other 42 were referred for adjuvant chemotherapy or recurrence. The clinicopathologic characteristics were evaluated for association with relapse or death. Results: Median age was 24 years (range, 11-76 years). Forty-nine (39.8%) had dysgerminomas, 35 (28.5%) had immature teratomas, 12 (9.8%) had mixed germ cell tumors, 26 (21.1%) had yolk sac tumors, and 1 (0.8%) had embryonal carcinoma. International Federation of Gynecology and Obstetrics stage distribution was as follows: stage I, 87 (70.7%); stage II, 3 (2.4%); stage III, 29 (23.6%); and stage IV, 4 (3.3%). Fertility-sparing surgery was performed in 92 patients, whereas the remaining 31 received radical surgery; 65.8% of patients received adjuvant chemotherapy. Recurrence rate was 17.8% and the median time to recurrence was 9 months. Univariate and multivariate analyses showed that patient age (>45 years) and treatment outside a referral (MITO) center were the most important predictors of recurrence. The 5-year overall survival rate was 88.8%, with a median follow-up of 61 months. Univariate and multivariate analyses demonstrated that stage greater than I and yolk sac tumors were independent poor prognostic indicators. Conclusions: This study confirms that MOGCTs have excellent prognosis, with 5-year overall survival rates of 95.6% and 73.2% in stage I and advanced stages, respectively. Age older than 45 years and treatment not in a referral center are independent risk factors for recurrence, whereas stage greater than I and yolk sac histology are independent poor prognostic indicators.

Ovarian Sertoli-Leydig cell tumors. A retrospective MITO study

OBJECTIVE To evaluate clinicopathologic features and to investigate the outcome of patients with ovarian Sertoli-Leydig cell tumors (SLCTs). METHODS Data concerning 21 patients treated in 11 MITO centers were retrospectively reviewed. RESULTS Median age was 37 (range 16-76). FIGO stage was: 17 (81%) IA, 1 (4.8%) IC, 1 (4.8%) IIB and 2 (9.5%) IIIC. Five patients (23.8%) had G1 tumor, ten (47.6%) had G2, and six (28.6%) had G3. Fertility-sparing operation was performed in 11 patients, while hysterectomy with bilateral salpingo-oophorectomy was executed in 10 patients; five patients received adjuvant chemotherapy (G2-3). Seven patients (33.3%) relapsed with a median time to recurrence of 14 months. Six recurrent patients had G2-3 disease, while one had G1. Four patients had stage IA disease, one IC and 2 stage IIIC. Patients with stage IA disease did not receive adjuvant chemotherapy. Two patients had pelvic recurrence, 4 abdominal (one with lymph nodal involvement), one on the contralateral ovary and the trocar access. Five patients underwent salvage surgery plus chemotherapy, while one received only salvage chemotherapy and one palliation. Five patients died of disease, four had received first treatment not in a MITO center. 5 year overall survival was 100% for patients with G1 disease and 77.8% for G2-3. 5 year overall survival was 92.3% for stage I and 33.3% for stage>I. CONCLUSIONS The prognosis of patients with grade 1 SLCT is excellent without adjuvant chemotherapy. Patients with advanced stage or grade 2-3 tumors appear to benefit from postoperative chemotherapy.

High-grade endometrial cancer: value of [18F]FDG PET/CT in preoperative staging

ObjectiveThe purpose of this study was to assess the value of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in the primary staging of high-risk endometrial cancer patients. MethodsThis retrospective study was conducted on 32 consecutive patients with histological diagnosis of primary high-risk endometrial cancer, who underwent PET/CT with [18F]FDG in addition to conventional clinical and instrumental staging procedures. After surgery, [18F]FDG PET/CT findings were correlated with pathological findings on a patient-by-patient basis. The diagnostic accuracy of [18F]FDG PET/CT for primary cancer detection, lymph nodal involvement and distant metastases was assessed. Results[18F]FDG PET/CT could correctly detect primary tumor in 29 of the 32 high-risk patients, with a sensitivity of 90.6%. The overall [18F]FDG PET/CT patient-based sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 57.1, 100.0, 100.0, 86.4, and 88.5%, respectively, for revealing lymph nodal neoplastic involvement, and 100.0, 96.0, 87.5, 100.0, 96.9%, respectively, for detecting distant metastases. In particular, while the suspicion of distant metastases was documented by conventional imaging in only two patients, [18F]FDG PET/CT correctly identified metastatic lesions in seven patients (21.9% of cases). ConclusionThe major benefit provided in high-grade tumor patients by the use of [18F]FDG PET/CT in the primary staging of endometrial cancer is its ability to accurately detect distant metastases in the abdomen and extra-abdominal regions. [18F]FDG PET/CT adds relevant information that may influence patient management.

Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience

OBJECTIVE Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for pure ovarian dysgerminoma (POD), except for correctly staged IA patients. The aim of study was to evaluate the outcome of IA POD patients with incomplete surgical staging in order to define the proper management. METHODS Data concerning primary treatment and recurrence were reviewed for 26 patients with stage IA POD treated in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. RESULTS Median age was 22.5years. Primary surgery was fertility sparing for 17 patients (65.4%) and radical surgery was performed in 9 patients due to older age or gonadal dysgenesis. Only five patients (19.2%) had complete surgical staging; 38.5% had lymph node dissection, 46.2% had peritoneal biopsies and/or omentectomy and 65.4% had peritoneal washing. Seven patients received adjuvant chemotherapy. Overall recurrence rate was 11.5%: all recurrences occurred in the group submitted to incomplete staging procedure. No patients treated with adjuvant chemotherapy relapsed. One patient had pelvic recurrence, one patient relapsed in the abdomino-pelvic peritoneum and lymph nodes and the third patient showed a peritoneum, lymph nodal and residual ovary relapse. All patients with recurrence were cured by salvage therapy: 2 patients were treated with surgery plus chemotherapy and one only with chemotherapy. After a median follow-up of 100months all patients are alive without evidence of disease. Six patients opted for conception and delivered healthy infants, two with IVF with donor oocyte. CONCLUSIONS IA POD prognosis is excellent. Conservative surgery with a complete surgical staging is the gold standard. Patients with incomplete staging could undergo surgical restaging or surveillance. Chemotherapy should be reserved to relapse with excellent chances of therapeutic success.

Recurrent granulosa cell tumors (GCTs) of the ovary: A MITO-9 retrospective study

OBJECTIVE Optimal treatment of recurrent GCTs is unknown. The aim of this study was to evaluate the characteristics of recurrent GCTs. METHODS Data on 35 recurrent GCTs were reviewed. RESULTS Initial FIGO stages were: 11 IA, 11 IC, 6 Ix, 1 IIB, 5 IIIC and 1 IV. All patients had undergone primary surgical treatment, and in 8 cases adjuvant chemotherapy was given. The median RFS was 53.2 months with differences between patients receiving (72.5 months) and not receiving (48 months) adjuvant chemotherapy and between patients optimally staged (64.5 months) or not staged (47 months). Recurrence sites were: pelvic, 13; abdominal, 6; lymph-nodal, 2; pelvic+abdominal, 7; abdominal+lymph-nodal, 4; and pelvic+lymph-nodal, 3. Twenty-five patients underwent debulking surgery+chemotherapy, 6 surgery, 2 surgery+radiotherapy, 1 chemotherapy and 1 palliation. 69% completed the chemotherapy. No difference was found in OS among patients receiving or not receiving chemotherapy after secondary surgery at recurrence and among the different relapse sites. Eleven patients developed a second relapse after a median time of 38 months. 81.8% had received adjuvant therapy at first recurrence. Four patients underwent surgery, 4 surgery+chemotherapy, 1 surgery+radiotherapy and 2 palliation. Four patients developed a third recurrence after a median time of 41 months. Two patients received chemotherapy and 2 hepatic resection. Nine patients (25.7%) died of disease. 5y-OS from the first recurrence was 55.6% and 87.4% for patients with or without residual tumor at subsequent debulking surgery, respectively. CONCLUSIONS In GCTs surgery remains the cornerstone treatment at relapse. RFS was higher in patients who received adjuvant therapy after initial diagnosis, with no difference in OS.

External Validation of the Endometriosis Fertility Index (EFI) for Predicting Spontaneous Pregnancy after Surgery: Further Considerations on Its Validity

Background/Aims: The revised American Society for Reproductive Medicine classification of endometriosis has a limited predictive value for pregnancy after surgery. A tool for predicting spontaneous pregnancy or pregnancy following assisted reproduction technology (ART) represents a clinical need. This study aimed to (i) provide an external validation of the EFI score in predicting pregnancy in infertile Italian endometriosis women; (ii) evaluate the predictive value of EFI score on ART outcome for patients who previously attempted to spontaneously conceive after surgery. Methods: In 104 women with endometriosis, EFI score was calculated based on a prospective database data. Cumulative pregnancy rates curves were calculated using Kaplan-Meier (K-M) product limit estimate and log-rank test was used to evaluate differences between EFI groups. A receiver operating characteristic (ROC) curve was plotted for EFI as a predictor of ART outcome. Results: Differences in time to non-ART pregnancy for the six EFI groups were statistically significant (log-rank, p = 1.4 × 10-4). The area under the curve (AUC) for EFI as ART outcome predictor was 0.75 (95% CI 0.61-0.89, p = 6.2 × 10-3), while the best cut-point for pregnancy was 5.5. Conclusion: The EFI score is a reliable scoring system to predict non-ART and ART pregnancy outcome after surgery for endometriosis.

Management of bilateral malignant ovarian germ cell tumors: a MITO-9 retrospective study.

Objectives Bilaterality is rare in malignant ovarian germ cell tumors (MOGTs). The bilateral ovarian involvement represents a critical issue when diagnosed in young women desiring to preserve fertility. The aim of this study was to evaluate clinical characteristic and management of patients bilateral MOGTs. Methods Patients affected by bilateral MOGT and treated at MITO group centers were reviewed. Results In 145 patients with MOGTs, 5.5% were bilateral. Three patients were affected by dysgerminoma (associated with bilateral gonadoblastoma in 1), 2 by immature teratoma, 2 by mixed germ cell tumors, and 1 by embryonal carcinoma. International Federation of Gynecology and Obstetrics stage was 3 IB, 1 IC, 3 IIIC, and 1 IV. Three patients received radical surgery, and the patient with dysgerminoma associated with gonadoblastoma received bilateral adnexectomy. Four patients received fertility-sparing surgery; 2 patients received unilateral salpingo-oophorectomy and contralateral cystectomy; in 2 patients, the ovaries were completely transformed in neoplastic tissue; suspecting a contralateral dysgerminoma histology, a unilateral salpingo-oophorectomy and contralateral biopsy were performed, and the contralateral neoplastic ovary was left unresected. Six patients received adjuvant chemotherapy. Seven patients are disease free after a median follow-up of 54 months. The patient affected by embryonal carcinoma died of disease. Two patients resumed menstruation, and one had a pregnancy. A compromised ovarian function was found in 2 patients, and they were addressed to oocyte cryopreservation. Conclusions Bilateral MOGTs have a good prognosis. In dysgerminoma histology, residual disease could be left to spare fertility. An oncological and reproductive function follow-up is recommended.

Fertility preservation in female cancer patients: a single center experience

Advances in cancer treatment allow women to be cured and live longer. However, the necessary chemotherapy and radiotherapy regimens have a negative impact on future fertility. Oncofertility has emerged as a new interdisciplinary field to address the issue of gonadotoxicity associated with cancer treatment and to facilitate fertility preservation, including oocyte and ovarian tissue cryopreservation. These fertility issues are often inadequately addressed, and referral rates to oncofertility centers are low. The aim of this study was to report the 3-year experience of the San Raffaele Oncofertility Unit. A total of 96 patients were referred to the Oncofertility Unit for evaluation after the diagnosis of cancer and before gonadotoxic treatment between April 2011 and June 2014. Of the 96 patients, 30 (31.2%) were affected by breast cancers, 20 (20.8%) by sarcomas, 28 (29.2%) by hematologic malignancies, 13 (13.5%) by central nervous system cancers, 3 (3.1%) by bowel tumors, 1 (1.0%) by Wilms’ tumor, and 1 (1.0%) by a thyroid tumor; 47 (49.0%) were referred for oocyte cryopreservation before starting chemotherapy, 20 (20.8%) were referred for ovarian tissue cryopreservation, and 29 (30.2%) were not recruited. The mean time between the patients’ counseling and oocyte retrieval was 15 days (range, 2–37 days). The mean time between the laparoscopic surgery and the beginning of treatment was 4 days (range, 2–10 days). The number of patients who were referred increased over time, whereas the rate of patients who were not recruited decreased, showing an improvement in referrals to the Oncofertility Unit and in the patients’ counseling and understanding. Our results indicate that an effective multidisciplinary oncofertility team is necessary for prompt referrals and treatment.

The role of staging and adjuvant chemotherapy in stage I Malignant ovarian germ cell tumors (MOGTs): the MITO-9 study

Background Surgery followed by platinum-based chemotherapy is the standard of care for MOGCTs, except for stage IA dysgerminoma and stage IA grade 1 immature teratoma where surveillance only is recommended. The role of adjuvant chemotherapy and surgical staging is debated. Patients and methods Data from 144 patients with stage I MOGTs were collected among MITO centers (Multicenter Italian Trials in Ovarian Cancer) and analyzed. Results Fifty-five (38.2%) patients were affected by dysgerminomas, 49 (34%) by immature teratomas, 26 (18.1%) by yolk sac tumors and 14 (9.7%) by mixed tumors. Seventy-three (50.7%) patients receive surgery plus chemotherapy, while 71 (49.3%) patients underwent surgery alone. The latter group included 32 dysgerminomas (14 IA-13 Ix, 3 IB, and 2 IC), 34 immature teratomas (20 1A-13 IA grade 1, 6 Ix, 1 IB, and 7 IC), 4 mixed tumors and 1 yolk sac tumor. Forty-four patients did not received chemotherapy, even if it would have been indicated by recommended approach. 94 (65.3%) patients received peritoneal surgical staging. Twenty-three (15.9%) developed a recurrence. Incomplete surgical staging was associated with recurrence (P < 0.05; OR 2.37) at Cox regression analysis. Seven patients died. Four patients were affected by yolk sac tumors, two by mixed tumors and one by immature teratoma. Five patients died for disease, one for acute leukemia and one for suicide. Prognostic parameter analyses showed that yolk sac component is a predictor for survival (P < 0.05). Five-years OS rates were 96.8% and 88.7% in the surgically staged and the incomplete staged group, respectively, while 93.8% and 94.1% in the standard treatment and in the surveillance group, respectively. Conclusions This study shows that surveillance seems not to affect survival; chemotherapy should be reserved for relapse resulting in high cure rate. Incomplete peritoneal surgical staging is associated with recurrence. Yolk sac histology worsens the prognosis.