Early-stage clear cell ovarian cancer compared to high-grade histological subtypes: An outcome exploratory analysis in two oncology centers.

OBJECTIVE: advanced stage clear cell ovarian cancer (CCOC) carries a higher risk of relapse and death compared to other histological subtypes. The prognosis of early-stage CCOC is controversial. METHODS: Early-stage high-grade OC patients from two Italian oncologic centers were included. Patients with early-stage CCOC were compared with those with high-grade endometrioid (HGE) and serous (HGS) OC in terms of relapse-free interval (RFI), cancer-specific survival (CSS) and post relapse cancer-specific survival (prCSS). The Cox proportional hazard model and the restricted mean survival time were used. RESULTS: Between 1981 and 2012, 134 patients with CC, 152 with HGE and 160 with HGS were treated at two referral centers. Median follow-up was 11.5 years. Ten years RFI rates were 80.6%, 72.1%, 60.6%, and CSS rates were 84.3%, 82.6%, 81.7% respectively. Adjuvant chemotherapy significantly improved RFI (aHR 0.61, 95%CI 0.40 to 0.91, P = 0.015). In the multivariable analysis HGS histotype was associated with a shorter RFI compared to CC, (Hazard Ratio [HR]: 1.81; 95%CI: 1.12-2.93; P = 0.016), whereas CSS was not statistically different. prCSS was longer in HGS compared to CCOC (HR, 0.36; 95% CI, 0.17-0.74; P = 0.006). According to the stage, IA/IB/IC1 HGSOC had a shorter RFI (HR, 2.13; 95% CI, 1.14-3.99; P = 0.018) compared to IA/IB/IC1 CCOC, but similar CSS. For prCSS, CC compared to HGS conferred a worse prognosis regardless of the initial stage. CONCLUSIONS: Early-stage CCOC is associated with a longer RFI, similar CSS and a shorter prCSS compared to HGSOC. No prognostic differences were observed between CC and HGE OC. The relapse risk was the lowest in IA/IB/IC1 CC compared to HGS, whereas CC displayed poor sensitivity to chemotherapy after relapse.

Ovarian function, fertility, and menopause occurrence after fertility-sparing surgery and chemotherapy for ovarian neoplasms.

BACKGROUND: The effect of chemotherapy exposure (CE) on ovarian function in young women with ovarian neoplasms undergoing fertility-sparing treatment (FST) remains unclear. We investigated whether CE is correlated with the outcomes (1) during-treatment and (2) post-treatment amenorrhea, (3) conception rate, (4) pregnancy outcome, and (5) spontaneous menopausal age. PATIENTS AND METHODS: Eligibility criteria were patients with a diagnosis of epithelial (EOC) or nonepithelial (no-EOC) invasive ovarian neoplasm, premenopausal age, undergoing FST ±â€¯CE, histopathology confirmation, and adequate follow-up. The groups' outcomes were compared by logistic and linear regression analysis. RESULTS: A total of 548 patients diagnosed during 1980 and 2014 were included, 198 in the EOC group and 350 in the no-EOC group, and 44% received chemotherapy, with a median follow-up of 15.9 years. In no-EOC patients, CE conferred a higher risk for Outcomes 1 (adjusted OR [aOR] 27; 95% CI 12 to 61; P < .0001) and 2 (aOR 5.42; 95% CI 1 to 24; P = .0256) and was associated with a younger menopausal age (adjusted ß -5.52; 95% CI -10.53 to -0.52; P = .0313). Overall, 57% of patients attempted pregnancy, with a conception rate of 89%. In EOC patients, no association between CE and a decreased fertility was demonstrated (aOR, 3.05; 95% CI 0.72 to 12.88; P = .1298). CONCLUSIONS: CE in no-EOC was associated with an increased risk of during-treatment amenorrhea, post-treatment amenorrhea, and earlier spontaneous menopausal age; CE in EOC was not associated with any item at study. Patients undergoing FST had reassuringly high conception rates and low premature ovarian failure rates; however, in pretreatment counseling, the risks of this approach in such young population should be discussed.

Role of 18 F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in malignant ovarian germ cell tumors: a single-center experience with long term follow-up.

INTRODUCTION: 18F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a diagnostic tool widely used in oncology, but to date there are no established recommendations for its use in malignant ovarian germ cell tumors. The aim of this study was to evaluate the role of 18F-FDG PET/CT in the clinical management of patients with malignant ovarian germ cell tumors. METHODS: This was a retrospective review of 18F-FDG PET/CT scans performed in patients diagnosed with malignant ovarian germ cell tumors treated at the gynecology department of San Gerardo Hospital (Monza, Italy) from June 2006 to December 2016. Data collected included clinical history, radiological, biochemical and pathological evaluation, treatment, follow-up, outcome, and clinical indication for the PET/CT scan. PET/CT findings were categorized as negative/normal (no abnormal FDG uptake or physiological uptake), positive/abnormal (FDG uptake considered to indicate active germ cell malignancy), or equivocal (FDG uptake of uncertain significance, not clearly correlated to neoplastic disease). RESULTS: A total of 69 PET/CT scans in 37 patients were evaluated. The mean age at diagnosis was 25 years (range 20-48). The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage I (22/37) disease and had a diagnosis of dysgerminomas (18/37). Imaging indications were initial staging before treatment (4/69, 6%), staging after inadequate staging surgery (24/69, 35%), restaging after adjuvant chemotherapy (17/69, 25%), relapse suspect (9/69, 13%), and follow-up (15/69, 21%). Pathology confirmation of PET/CT results was available in 28/69 (40.5%) studies. All negative PET/CT (15/28) cases were confirmed with laparoscopy as true negative; among 13/28 positive PET cases, histopathology confirmed 7 (54%) as true positive and 6 (46%) as false positive (5 inflammatory and 1 mature teratoma implants). Patient-based analysis showed 100% sensitivity, 71% specificity, 54% positive predictive value, 100% negative predictive value, and 79% accuracy. Clinical follow-up was available in 41 (59.4%) of 69 PET/CT images: 28/41 studies were negative and 13/41 positive. A mean follow-up of 28 months (median 15, range 5-102) confirmed negative PET/CT studies. A total of 13 positive PET/CT patients underwent chemotherapy with subsequent evidence of disease response. DISCUSSION: PET/CT in malignant ovarian germ cell tumors was mainly performed for staging after inadequate staging surgery or for restaging after adjuvant chemotherapy. PET/CT was associated with high sensitivity and negative predictive value.

Long-term results of fertility-sparing treatment compared with standard radical surgery for early-stage epithelial ovarian cancer.

BACKGROUND: The objective of this study is to evaluate the safety of fertility-sparing surgery (FSS) for early-stage epithelial ovarian cancer (EOC). METHODS: A retrospective analysis was performed to identify patients treated for early-stage EOC and to compare the clinical outcomes of patients treated with FSS and radical surgery (RS). RESULTS: A total of 1031 patients were treated at two Institutions, 242 with FSS (group A) and 789 with RS (group B). Median duration of follow-up was 11.9 years. At univariate analyses, FSS was associated with decreased risk of relapse (P=0.002) and of tumour-related death (P=0.001). Multivariate analysis did not confirm the independent positive role of FSS neither on relapse-free interval (RFI) nor on cancer-specific survival (CSS). Tumour grade was associated with shorter RFI (P<0.001) and shorter CSS (P=0.001). The type of treatment did not influence CSS or RFI in any grade group. We also found a significant association between low-grade tumours and younger age. CONCLUSIONS: Fertility-sparing surgery is an adequate treatment for patients with stage I EOC. The clinical outcome of patients with G3 tumours, which is confirmed to be the most important prognostic factor, is not determined by the type of treatment received.

Long-Term Clinical Benefits of Neoadjuvant Chemotherapy in Women With Locally Advanced Cervical Cancer: Validity of Pathological Response as Surrogate Endpoint of Survival.

OBJECTIVE: Neoadjuvant chemotherapy (NACT) is a valid treatment option for women with locally advanced cervical cancer (LACC). This study aims to evaluate the impact of sociodemographic factors, clinical factors, and NACT regimens on survival endpoints. The role of pathological response to NACT as a surrogate endpoint of survival was also assessed. MATERIALS AND METHODS: Retrospective analysis of consecutive sample data from women with LACC (stages Ib2-IVa) who underwent NACT followed by radical surgery was performed. Response was classified as optimal response (including complete response and optimal partial response), suboptimal partial response, stable disease, and progressive disease. RESULTS: Four hundred forty-six women who had undergone surgery from 1992 to 2011 were analyzed. The overall optimal response was 35.4%. At a median follow-up of 12.7 years, 165 women (37.0%) experienced recurrence or died. Increase in patient age at surgery, International Federation of Gynecology and Obstetrics stage III/IV versus stage Ib2, and lymph-node positivity versus negativity seemed to impact negatively on survival, whereas neoadjuvant platinum-Taxol-containing regimens (compared with platinum-based regimens) improved survival. Response to NACT could be considered a surrogate endpoint of survival. CONCLUSIONS: Age, International Federation of Gynecology and Obstetrics stage III/IV, lymph-node involvement, and type of NACT administered have a significant impact on survival. Response to NACT is a good surrogate endpoint of survival in patients with LACC.

Outcome of patients with stage I immature teratoma after surveillance or adjuvant chemotherapy.

Objective: Immature teratomas are rare malignant ovarian germ cell tumours, typically diagnosed in young women, where fertility-sparing surgery is the treatment of choice. The role of adjuvant chemotherapy in stage I disease remains controversial. We evaluated the impact of surveillance versus chemotherapy on the recurrence rate in stage I immature teratomas. Methods: We collected a single centre retrospective series of patients with stage I immature teratomas treated with fertility-sparing surgery at San Gerardo Hospital, Monza, Italy, between 1980 and 2019. Potential risk factors for recurrence were investigated by multivariate logistic regression. Results: Of the 74 patients included, 12% (9/74) received chemotherapy, while 88% (65/74) underwent surveillance. Median follow-up was 188 months. No difference in recurrence was found in stage IA/IB and IC immature teratomas [10% (6/60) vs. 28.6% (4/14) (P=0.087)], grade 1, grade 2, and grade 3 [7.1% (2/28) vs. 14.3% (4/28) vs. 22.2% (4/18) (p=0.39)], and surveillance versus chemotherapy groups [13.9% (9/65) vs. 11.1% (1/9)) (p = 1.00)]. In univariate analysis, the postoperative approach had no impact on recurrence. The 5-year disease-free survival was 87% and 90% in the surveillance and chemotherapy groups, respectively; the overall survival was 100% in both cohorts. Conclusions: Our results support the feasibility of surveillance in stage I immature teratomas. Adjuvant chemotherapy may be reserved for relapses. However, the potential benefit of chemotherapy should be discussed, especially for high-risk tumours. Prospective series are warranted to confirm our findings. What is already known on this topic: To date, no consensus has been reached regarding the role of adjuvant chemotherapy in stage I immature teratomas of the ovary. Some studies suggest that only surveillance is an acceptable choice. However, guidelines are not conclusive on this topic. What this study adds: No difference in terms of recurrence was observed between the surveillance and the adjuvant chemotherapy group. All patients who relapsed were successfully cured with no disease-related deaths. How this study might affect research practice or policy: Adjuvant chemotherapy should be appropriately discussed with patients. However, it may be reserved for relapse according to our data.

Delivery delay with neoadjuvant chemotherapy for cervical cancer patients during pregnancy: a series of nine cases and literature review.

OBJECTIVE: Treatment of locally invasive cervical cancer diagnosed during pregnancy in women who desire to retain their pregnancy is a major challenge to physicians. Neoadjuvant chemotherapy followed by radical hysterectomy has been reported to be an attractive option to delay delivery until fetal viability has been reached. METHODS: Between 1994 and 2009 9 patients were treated at San Gerardo Hospital (Monza, Italy) for cervical cancer during pregnancy. RESULTS: FIGO stage was IB1 in four patients and IB2 in five. Tumor diameter ranged between 20 and 70 mm. After neoadjuvant platinum-based chemotherapy partial response was achieved in 5 patients, while 4 had a stable disease. One patient received a second-line chemotherapy during pregnancy due to progressive disease, achieving a partial response. Median duration of therapy delay until cesarean section was 16 weeks. Between 30 and 36 weeks of gestation all patients underwent cesarean section. Piver II radical hysterectomy with pelvic lymphadenectomy was performed. Two children had mild perinatal morbidities and were discharged in good conditions after 14 and 40 days. Three patients received adjuvant therapy for pathological risk factors. Four patients relapsed (44%) and two of them (23%) died because of tumor progression. CONCLUSION: During pregnancy, the oncological outcome of cervical cancer patients is similar to non-pregnant ones. Chemotherapy does not seem to affect fetal health and development, even if longer follow-up is required. Therefore, neoadjuvant chemotherapy for the treatment of locally invasive cervical cancer during pregnancy seems to be a reasonable option for delay definitive treatment until fetal viability is obtained.

Gestational Intraplacental Choriocarcinoma in a Term Pregnancy: A Case Report.

Intraplacental choriocarcinoma (IC) is a rare type of gestational choriocarcinoma (GC) occurring within the placenta, and only a small number of cases have been reported so far. Intraplacental choriocarcinoma is usually asymptomatic or may present with aspecific symptoms, including unexplained vaginal bleeding during pregnancy. Early diagnosis and treatment are pivotal for ensuring optimal outcomes. However, intraplacental choriocarcinoma is rarely suspected due to limited knowledge and awareness of the condition. Here, we report the case of a 34-year-old woman diagnosed with intraplacental choriocarcinoma by placental histological examination performed after delivery due to unexplained vaginal bleeding at 29 gestational weeks, requiring hospital admission. Two lines of chemotherapy and surgery were necessary to achieve complete remission. Since unexplained vaginal bleeding during pregnancy can be a clinical manifestation of intraplacental choriocarcinoma, we propose to consider placental histological examination in all pregnancies with this complication.

Weekly epirubicin in the treatment of gestational breast cancer (GBC).

BACKGROUND: GBC is a rare disease and chemotherapy in this setting lacks a standardized approach. PATIENTS AND METHODS: Patients 16-30 weeks pregnant with locally advanced/metastatic disease or with high risk of recurrence after surgery were evaluated. RESULTS: Twenty patients received weekly epirubicin 35 mg/m(2). Median maternal age was 37 years (23-42). Median gestational age at chemotherapy was 19 weeks. Thirteen patients were treated after surgery while 7 had locally advanced tumours of which one had liver metastases. Mean total epirubicin dose was 420 mg/m(2) with a median number of 12 administrations (4-16). No grade 3-4 toxicities were observed. No foetal adverse events were observed except 1 premature delivery at 28 weeks. Births were induced by caesarean section in 12 patients at a median gestational age of 35 weeks. No malformations were reported except 1 newborn with polycystic kidney. At a median age of 2 years, neurological, cardiological and immunological development was normal in all children as reported by their parents. In 7/20 patients with evaluable disease, five had an objective response. At a median follow-up of 38 months, 17 patients are alive; 14 are disease free. CONCLUSIONS: Weekly epirubicin appears safe and effective with low foetal toxicity and could be considered in GBC.

Oncologic and fertility impact of surgical approach for borderline ovarian tumours treated with fertility sparing surgery.

BACKGROUND: Even if borderline ovarian tumours (BOTs) in young women treated with fertility-sparing treatment (FST) have an excellent outcome, the type of surgery might affect relapse and fertility. We investigated the effect of surgical approach (open surgery vs. laparoscopy) and type of surgery (salpingo-oophorectomy [SO] vs. cystectomy [Cy]) on oncologic and fertility outcomes in patients with BOT. PATIENTS AND METHODS: Patients with BOT treated at San Gerardo Hospital, Monza, with FST in 1978-2013 period were included. Cox models, stratified by decade of surgery, were used to investigate the association between time to first recurrence or conception and clinical factors. RESULTS: Among 535 patients included, 271 underwent unilateral SO and 264 underwent Cy. Median follow-up was 13.5 years. Ten-year (10-yr) recurrence rate was 23% (95% confidence interval [CI]: 18-29%) for SO and 31% (95% CI: 24-38%) for Cy group (P = 0.10) in patients with unilateral tumour, whereas it was 62% (95% CI: 44-79%) and 72% (95% CI: 59-84%), respectively, (P = 0.35) in patients with bilateral tumour. Multivariable analysis showed no association between recurrence and surgical approach (P = 0.44), type of surgery (P = 0.06) and a negative association with advanced stage (hazard ratio [HR] = 3.18; 95% CI: 2.11-4.78; P < 0.001) and bilateral tumours (HR = 2.48; 95% CI: 1.78-3.47; P < 0.001). Among 252 patients (47.1%) with pregnancy desire, multivariable analysis showed no association between conception success and the type of surgery, surgical approach, histology and tumour laterality. Fertility after surgery was positively associated with prior pregnancy (HR = 1.68; 95% CI: 1.17-2.41; P = 0.005) and negatively associated with the number of surgical procedures (HR = 0.62; 95% CI: 0.53-0.73; P < 0.001). CONCLUSIONS: The type of surgical procedures did not influence recurrence rate or fertility. However, additional surgical procedures decreased the fertility potential. These data can support clinicians in tailoring the best strategy for FST in young patients with BOT.

Neoadjuvant chemotherapy and conservative surgery for stage IB1 cervical cancer.

OBJECTIVES: To assess the effectiveness of chemo-surgical conservative therapy for stage IB1 cervical tumors in patients desiring to preserve fertility. METHODS: From 1995 to April 2007 51 nulliparous patients with tumor 3 mm in 4. Four women deemed ineligible for conservative surgery after chemotherapy and one refusing to preserve her genital apparatus underwent radical hysterectomy. After a median follow-up of 69 months no relapses were observed. Nine women attempted to conceive: ten pregnancies occurred in 6 patients and 9 live babies have been born, while one woman experienced a first-trimester miscarriage. CONCLUSIONS: The high rate of pathological response confirms the effectiveness of the preoperative treatment for reducing the tumor volume allowing the removal only of a cervical cone instead of the entire cervix with cardinal ligaments as needed by radical trachelectomy. Successful pregnancies are possible after such integration.

Endometrioid-like yolk sac and Sertoli-Leydig cell tumors in a carrier of a Y heterochromatin insertion into 1qh region: a causal association?

We describe the case of a young woman showing yolk sac tumors (YST) and a Sertoli-Leydig cell tumor (SLCT) in the right ovary, with recurrences in the right adnexum and with hepatic metastasis. To our knowledge, YST and SLCT have never been described as components of the same tumor or reported as associated in the same patient. The patient's karyotype showed the presence of Y chromosome inserted into the 1qh region; the inserted region corresponded to Yq12 heterochromatin. LOH analysis revealed 1p36 paternal allele loss in the proband tumor, thus supporting a germ cell origin for the tumor. The presence of Y heterochromatin in 1qh DNA might induce disturbances in the normal regulation of oncogenes located in 1q.

International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer.

BACKGROUND: The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer. METHODS: Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided. RESULTS: Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%). CONCLUSION: These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer.

Placental site trophoblastic tumor: an overview.

OBJECTIVE: To analyze 15 consecutive cases of placental site trophoblastic tumor seen in a single reference institution for gestational trophoblastic disease, San Gerardo Hospital, Monza, Italy. STUDY DESIGN: Consecutive patients affected by placental site trophoblastic tumors were selected from our computerized database. RESULTS: There were 15 patients with placental site trophoblastic tumor, with a median age of 35 years. The antecedent pregnancy was a term one in 6 cases (40%), a miscarriage in 4 cases (27%), a termination in 2 cases (13%) and a molar abortion in 2 cases (13%). In 1 case the previous pregnancy was unrecognized. The median interval from the last pregnancy was 12 months, and the presenting symptom in 11 cases was vaginal bleeding, in 2 cases amenorrhea, in 1case a nephrotic syndrome and in 1 case, presenting with metastatic disease, hemoptysis. Six patients were treated using neoadjuvant chemotherapy with etoposide/methotrexate/actinomycin-etoposide/ vincristine (EMA-CO) followed in 5 of 6 (83%) cases by hysterectomy. One patient had only medical treatment with EMA-CO because of a strong desire for or childbearing and had a complete response; after 15 months she was free from disease. The last 9 patients underwent surgery as the first therapy. Among these patients 1 had presented with metastatic pulmonary disease and underwent chemotherapy, with complete disappearance of the pulmonary lesions. Two of these 9 patients had a relapse; the mirst patient had a pelvic and bladder relapse, and 14 months after multiple chemotherapy and surgery, she died. The second had a suburethral relapse 2 months after initial surgery; after chemotherapy and surgery she was well and free of disease. CONCLUSION: Our experience suggests that the role of chemotherapy may be reconsidered not only for metastatic disease but als of or uterine disease when choosing conservative management in young, fertile patients who desire childbearing. Chemotherapy may play an important role in avoiding relapse or early metastases even in patients who underwent hysterectomy as primary treatment.

Randomized phase III clinical trial evaluating weekly cisplatin for advanced epithelial ovarian cancer.

This randomized, open label, phase III clinical trial (1988-1992) compared the efficacy and safety of a dose-dense regimen of single-agent cisplatin with a standard 3-weekly schedule in first-line chemotherapy for advanced epithelial ovarian cancer. Two hundred eighty-five patients were randomly assigned to the experimental dose-dense arm (cisplatin 50 mg/m(2) weekly × nine cycles) or to the control (standard treatment) arm (cisplatin 75 mg/m(2), administered on day 1 every 21 days × six cycles). The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall response to chemotherapy, and toxicity. Toxicity and response to treatment were compared with the χ(2) test using trend or exact correction. PFS and OS were estimated by Kaplan-Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 16.8 years, no differences were observed between the two treatments in PFS (experimental arm: 17.2 months; control arm: 18.1 months; HR = 1.08, 95% confidence interval [CI] = 0.83 to 1.40; P = .57) and in OS (experimental arm: 35 months; control arm: 32 months; HR = 0.97, 95% CI = 0.75 to 1.26; P = .97). Thus, increasing dose intensity of cisplatin does not improve PFS or OS compared with standard chemotherapy.