Experimental drugs for fallopian cancer: promising agents in the clinical trials and key stumbling blocks for researchers.

INTRODUCTION: Fallopian tube carcinoma (FC) as a single entity is a rare disease. Although its diagnosis is increasing thanks to the widespread use of prophylactic salpingectomy, there are no clinical trials exclusively designed for FC. AREAS COVERED: This review aims at identifying the most promising trials and future therapeutic pathways in the setting of FC. EXPERT OPINION: Hot topics in FC treatment include the consequences of using PARP inhibitors (PARPi) as first-line therapy, ways to overcome platinum resistance, and the role of immunotherapy. Patient selection is a key point for future development of target therapies. Next-generation sequencing (NGS) is one of the most investigated technologies both for drug discovery and identification of reverse mutations, involved in resistance to PARPi and platinum. New, promising molecular targets are emerging. Notwithstanding the disappointing outcomes when used by itself, immunotherapy in FC treatment could still have a role in combination with other agents, exploiting synergistic effects at the molecular level. The development of cancer vaccines is currently hampered by the high variability of tumor neoantigens in FC. Genomic profiling could be a solution, allowing the synthesis of individualized vaccines.

Synergic role of preoperative 18F-fluorodeoxyglucose PET and MRI parameters in predicting histopathological features of endometrial cancer.

BACKGROUND: The aim of the present study is to explore the correlation between PET and MRI parameters of primary tumour and clinicopathological features and to determine their synergic predictive role in patients with endometrial cancer candidate to surgery. METHODS: Retrospective study including 27 patients with endometrial cancer and preoperative 18F-fluorodeoxyglucose (18F-FDG)-PET and MRI scan. The following parameters, calculated on the primary tumour, were used for analysis: maximum standardized uptake value (SUVmax), SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) for PET scans; mean apparent diffusion coefficient (ADCmean) and volume index for MRI scans. FIGO stage, grade, histotype, lymphovascular space invasion (LVSI) and myometrial invasion were the considered clinicopathological features. RESULTS: MRI volume index was a good predictor for deep myometrial invasion [area under the curve (AUC) = 0.85; P = 0.003] and for LVSI (AUC = 0.74; P = 0.039). A cutoff value of 9.555 for MRI volume index was predictive for deep myometrial invasion (sensitivity = 84.6%; specificity = 76.9%); a cutoff of 12.165 was predictive for LVSI (sensitivity = 69.2%; specificity = 83.3%). A TLG cutoff value of 26.03 was predictive for deep myometrial invasion (sensitivity = 84.6%; specificity = 76.9%). A high-direct correlation was found with MRI volume index (rho = 0.722; P < 0.001); low-direct correlation with SUVmax (rho = 0.484; P = 0.012), SUVmean (rho = 0.47; P = 0.015) and TLG (rho = 0.482; P = 0.013) were identified. The SUVmax/ADCmean ratio showed a low-direct correlation with percentage of myometrial invasion (rho = 0.467; P = 0.016). CONCLUSION: Volume index, TLG and SUVmax/ADCmean ratio are associated with deep myometrial invasion. As myometrial invasion is the index used to predict lymph node involvement in endometrial cancer, the synergic use of these imaging parameters may be suggested to predict lymphnodal metastases.

Different Patterns of Disease Spread between Advanced-Stage Type I and II Epithelial Ovarian Cancer.

BACKGROUND AND AIMS: Two types of epithelial ovarian carcinoma (EOC) have been recently distinguished. Type I comprises low-grade serous, endometrioid and clear-cell tumors. High-grade endometrioid and serous tumors belong to type II. The aim of this study was to compare patterns of disease spread in advanced-stage type I and II EOCs at primary surgery. METHODS: Surgical and pathological data of 233 patients with advanced-stage EOCs were collected, 42 with type I and 191 with type II. The two groups were compared for tumor localization at primary surgery. Intraoperative mapping of ovarian cancer (IMO) was used to assess tumor dissemination. RESULTS: Tumor involvement was significantly higher in the type II group for the following: peritoneum (68.1 vs. 40.5%, p < 0.001), pouch of Douglas (60.2 vs. 40.5%, p = 0.06), vesicouterine ligament (40.8 vs. 19%, p = 0.027), diaphragm (45.0 vs. 11.9%, p < 0.001), serosa of liver (17.2 vs. 4.8%, p = 0.05), omentum (81.1 vs. 59.5%, p = 0.007), mesentery (42.9 vs. 16.7%, p = 0.005), pleural effusions (19.4 vs. 4.6%, p = 0.01) and ascites (60.7 vs. 21.4%, p < 0.001). IMO levels were different between the two groups (p = 0.001). CONCLUSIONS: This study provides clinical evidence in favor of the dualistic model of carcinogenesis, since types I and II are characterized by different findings at primary surgery.

Hysteroscopic Resection in Fertility-Sparing Surgery for Atypical Hyperplasia and Endometrial Cancer: Safety and Efficacy.

STUDY OBJECTIVES: To evaluate the rate of intrauterine adhesions after hysteroscopic resection of hyperplastic and/or cancer areas and the efficacy of combined treatment. DESIGN: Observational retrospective study. SETTING: Patients affected by endometrial atypical hyperplasia of the endometrium or early stage endometrial carcinoma. PATIENTS: Twenty-three patients, up to 45 years of age. INTERVENTION: Conservative treatment based on hysteroscopic resection of hyperplastic and/or cancer areas and subsequent therapy with megestrol acetate 160 mg/day. METHODS AND MAIN RESULTS: Approximately 5% of endometrial cancers (ECs) are diagnosed in women younger than 40 years old, usually with a good prognosis. From 2010 to 2014, 23 patients, up to age 45 years, who were affected by endometrial cancer (EC) grade 1 or atypical complex hyperplasia (ACH) and who wished to preserve fertility, underwent conservative treatment based on hysteroscopic resection of the hyperplastic and/or cancer areas and subsequent therapy with megestrol acetate 160 mg/day. Data with regard to age, body mass index, symptoms, history of infertility, and previous assisted reproductive technologies attempts, obstetrics history, previous diagnosis of intrauterine sinechiae, hysteroscopic findings, duration of therapy, follow-up reports, and reproductive outcomes were collected and analyzed. Of the 23 patients enrolled in the study, 3 patients (13%) presented with an endometrioid EC grade 1, and 20 patients (87%) had ACH. Twelve patients (52.2%) had complete remission after 3 months of progestin therapy, 9 patients (39.1%) had a complete remission after 6 months, and 2 (8.7%) patients had remission after 9 months. Six patients underwent a second hysteroscopic resection. The 3 patients with an initial diagnosis of EC had complete remission after a mean of 4 months of high-dose progestin therapy; in patients with ACH, remission occurred after a mean of 3 months. In all patients, intrauterine adhesions were not detected at any follow-up diagnostic hysteroscopy. After a median follow-up time of 25 months (range 8-37), we registered 1 (4.3%) relapse of disease. A total of 7 pregnancies in 6 patients were counted, after an average time of 7.4 months (range 3-13 months) after the end of progestin therapy. CONCLUSIONS: Hysteroscopic resection of hyperplastic and/or cancer areas before high dosage progestin therapy seems to be a safe and effective approach in the management of ACH and in patients with early EC who wish to preserve fertility.

Investigational therapies currently in Phase II clinical trials for the treatment of pelvic serous carcinomas.

INTRODUCTION: Pelvic serous carcinomas (PSCs) are a controversial entity, which mostly comprise fallopian tube carcinoma (FTC), primary peritoneal carcinoma (PPC) and serous ovarian carcinoma (OC). Despite incremental attention towards understanding pelvic serous carcinogenesis, the gold standard treatment and survival rates have not substantially changed in these last decades. AREAS COVERED: This review summarizes and gives a critical overview of the ongoing Phase II trials investigating therapies for PSC. EXPERT OPINION: Several novel molecules have been developed and are currently under investigation for the treatment of PSC, including FTC, PPC and serous OC. The trend of novel targeted agents is one towards individualized, tailored therapy, based on the molecular and biological differences that characterize tumors that seem similar based solely on histological analysis. The task of developing new molecules is particularly difficult for PSC, given the recurrent development of new patterns of drug resistance. However, even if current research is focused towards identifying the best treatments for each woman with a molecularly defined disease, a deeper knowledge of the molecular biology and genetics underlying FTC and its relation as a precursor of PSC is needed.

Surgical treatment of elderly patients with endometrial cancer (≥ 65 years).

OBJECTIVES: To analyze operability, short-term morbidity and mortality in women aged 65 and older with endometrial cancer. MATERIALS AND METHODS: The study cohort consisted of 124 elderly patients, aged 65 and older, with endometrioid endometrial cancer. Patients' clinical data included age at diagnosis, body mass index, ASA (American Society of Anesthesiologists) status and comorbidities, surgical procedures, FIGO (International Federation of Gynecology and Obstetrics) stage, histologic type, occurrence of operative and postoperative complications, and long-term disease-specific survival. Patients were divided into two groups according to age: those < 75 years and those ≥ 75 years. The analysis was repeated for patients older than 80 years who represent the category most at risk for perioperative morbidities. RESULTS: All patients were referred to primary surgery (abdominal versus vaginal) with the exception of 3 patients. Factors affecting significantly the choice of intervention were age, body mass index, and the presence of comorbidities. No women died during the perioperative period. The rate of perioperative complications was significantly higher for the older group. In a logistic regression model, aged ≥ 75 years (but not aged ≥ 80 years), chronic lung disease and performing lymphadenectomy correlated with a higher probability of perioperative morbidities. Long-term disease-specific survival was significantly shorter only for women aged ≥ 80. CONCLUSION: Geriatric patients should not be denied surgical treatment because of perceived risks associated with chronologic age, since the removal of the uterus confers a survival benefit.

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

OBJECTIVE: The purpose of this study was to assess the value of 2-[F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([F]FDG PET/CT) in the primary staging of high-risk endometrial cancer patients. METHODS: This retrospective study was conducted on 32 consecutive patients with histological diagnosis of primary high-risk endometrial cancer, who underwent PET/CT with [F]FDG in addition to conventional clinical and instrumental staging procedures. After surgery, [F]FDG PET/CT findings were correlated with pathological findings on a patient-by-patient basis. The diagnostic accuracy of [F]FDG PET/CT for primary cancer detection, lymph nodal involvement and distant metastases was assessed. RESULTS: [F]FDG PET/CT could correctly detect primary tumor in 29 of the 32 high-risk patients, with a sensitivity of 90.6%. The overall [F]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, [F]FDG PET/CT correctly identified metastatic lesions in seven patients (21.9% of cases). CONCLUSION: The major benefit provided in high-grade tumor patients by the use of [F]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. [F]FDG PET/CT adds relevant information that may influence patient management.

Surgery in advanced borderline tumors.

Our retrospective study evaluates the role of conservative surgery, performed in 10 of 22 patients affected by advanced stage serous borderline ovarian tumor. Although patients who underwent conservative surgery had a higher recurrence rate (60% after conservative surgery and 8% after radical surgery), all patients are alive without evidence of disease.

Adjuvant treatment with concomitant radiotherapy and chemotherapy in high-risk endometrial cancer: a clinical experience.

OBJECTIVE: The concurrent use of radiotherapy (RT) and chemotherapy (CT) as adjuvant treatment after surgery in high-risk endometrial cancer has been generally considered cautiously. Recently some of us have reported preliminary data on the efficacy and tolerability of concomitant CT and RT. In this paper, we update our experience. METHODS: A total of 47 patients aged >18 years and <80 years with histological diagnosis of high-risk endometrial endometrioid carcinomas entered the study. Inclusion criteria were stages IC G3, IIB, IIIA (patients with positive washing without other unfavourable prognostic factors were omitted), IIIB and IIIC. The radiation plan consisted of a total dose of 50.4 Gy, given in five fractions per week (1.8 Gy: daily dose) for 6 weeks. Paclitaxel (P) at a dose of 60 mg/m(2) was infused intravenously in 250 mL of normal saline for 1 h once weekly during RT for 5 weeks. Three further cycles of Paclitaxel, at a dose of 80 mg/m(2), have been given weekly at the end of RT. RESULTS: There was no life-threatening toxicity. The overall 5-year relapse-free survival was 81.8% (95% CI, 65.2-90.9). The 5-year percent overall disease-specific survival was 88.4% (95% CI, 71.1-95.6). CONCLUSIONS: These results, based on a larger series, support our previous data: Paclitaxel plus RT may represent an effective and well-tolerated treatment in high-risk endometrial cancer patients.

Paclitaxel and concomitant radiotherapy in high-risk endometrial cancer patients: preliminary findings.

BACKGROUND: There is still much debate about the best adjuvant therapy after surgery for endometrial cancer (EC) and there are no current guidelines. Radiotherapy (RT) alone does not seem to improve overall survival. We investigated whether concomitant Paclitaxel (P) and RT gave better clinical results. METHODS: Twenty-three patients with high-risk EC (stage IIB, IIIA, IIIC or IC G3 without lymphadenectomy or with aneuploid tumor) underwent primary surgery and were then referred for adjuvant therapy. P was given at a dose of 60 mg/m2 once weekly for five weeks during RT, which consisted of a total radiation dose of 50.4 Gy. Three further weekly cycles of P at a dose of 80 mg/m2 were given at the end of RT. Overall survival and disease-free survival were calculated from the time of surgery. Patterns of failure were recorded by the sites of failure. RESULTS: A total of 157 cycles of P were administered both during radiotherapy and consolidation chemotherapy. Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3-28). Survival rate for all the patients was 78.2%. Overall survival for the patients who completed chemo-radiation was of 81%. In this group median time to recurrence was 19.2 months (range 3-28). All recurrences were outside the radiation field. Mortality rate was 14.2%. CONCLUSION: This small series demonstrates pelvic radiotherapy in combination with weakly P followed by three consolidation chemotherapy cycles as an effective combined approach in high risk endometrial carcinoma patients.