Medical treatment of patients with gynecologic cancer during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 pandemic, cancer care had to be reorganized; national and international recommendations were published to manage anticancer treatments safely and to reduce the risk of SARS-CoV-2 infection for patients and health workers. OBJECTIVE: To evaluate whether the adoption of recommendations for the management of patients with gynaecologic cancer receiving treatment during the pandemic resulted in containment of infections and continuing oncologic care. METHODS: Based on the published recommendations, and according to the local Health Direction guidelines, we developed and drafted a security protocol to modify access of patients with gynaecologic cancer to the "Fondazione Policlinico Agostino Gemelli-IRCCS, Rome" between February 1 and April 30, 2020 and compared results with the corresponding 3 months of 2019. RESULTS: Between February and April 2019, we registered 3254 admissions, including 2253 patients receiving intravenous chemotherapies, 298 receiving oral therapies, and 703 having hospital visits. Between February and April 2020, we registered 3213 admissions, including 2221 patients receiving intravenous chemotherapies, 401 receiving oral therapies, and 591 having hospital visits. Oral treatments and general visits were different in the two time periods (p<0.001). Despite the elevated patient flow, only one patient (0.1%) tested positive for COVID-19 and there were no cases among healthcare staff. CONCLUSIONS: Based on the adopted security protocol we provided continuity of care for all patients and limited the spread of the COVID-19 infection.

Radical Surgery in Advanced Cervical Cancer Patients Receiving Bevacizumab-Containing Chemotherapy: A "Real Life Experience".

BACKGROUND: Platinum-based chemotherapy plus bevacizumab is the new standard of care in stage IVB cervical cancer (CC) patients. In this new scenario, radical surgery could be offered in selected cases with an optimal clinical response. Potential surgical complications related to previous bevacizumab treatment have never been described before in this type of setting. METHODS: This is a single-institutional retrospective study on women with CC who received radical pelvic surgery after platinum-based chemotherapy (platinum-taxol) plus bevacizumab. RESULTS: Between April 2016 and September 2017, 15 patients with CC underwent radical surgery after bevacizumab-containing chemotherapy (platinum-taxol) at the Division of Gynecologic Oncology, Catholic University of the Sacred Heart in Rome, Italy.All patients received at least 3 cycles of treatment. Fourteen (93.4%) patients underwent radical hysterectomy, whereas 1 patient received pelvic anterior exenteration. Median operating time was 290 minutes (range, 220-400), and estimated blood loss was 250 mL (range, 50-1500). Median time of hospitalization was 5 days (range, 2-21). Pathological response in the cervix was complete in 3 cases and microscopic in 1 patient (26.7%). Intraoperative complications occurred in 3 cases: 2 vascular injuries and 1 ureteral injury. Three patients (20.0% of the whole series) experienced grade 3 complications.At last follow-up (median time, 9 months), the median overall survival is 13 months (range, 6-31): 7 (46.7%) women were free of disease, 8 (53.3%) patients progressed, and 3 of them died of disease. CONCLUSIONS: Radical surgery can be performed in women with CC previously treated with a bevacizumab-containing regimen.

Robotic Surgery in Elderly and Very Elderly Gynecologic Cancer Patients.

STUDY OBJECTIVE: To investigate the feasibility, safety, and short-term outcomes of robotic surgery (RS) for gynecologic oncologic indications (cervical, endometrial, and ovarian cancer) in elderly patients, especially women age 65 to 74 years (elderly group [EG]) compared with women age ≥75 years (very elderly group [VEG]). DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: Between May 2013 and April 2017, 204 elderly and very elderly patients underwent RS procedures for gynecologic malignancies. RESULTS: The median age was 71 years (range, 65-74 years) in the EG and 77 years (range, 75-87 years) in the VEG. The incidence of cardiovascular disease was higher in the VEG (p = .038). The EG and VEG were comparable in terms of operative time, blood loss, and need for blood transfusion. Almost all (98.5%) of the patients underwent total/radical hysterectomy, 109 patients (55.6% of the EG vs 48.3% of the VEG) underwent pelvic lymphadenectomy, and 19 patients (10.5% of the EG vs 6.7% of the VEG) underwent aortic lymphadenectomy. A total of 7 (3.4%) conversions to open surgery were registered. Only 3 patients required postoperative intensive care unit admission. The median length of hospital stay was 2 days in each group. A total of 11 patients (5.6%) had early postoperative complications. Four patients (2.8%) in the EG and 2 patients (3.3%) in the VEG experienced grade ≥2 complications. At the time of analysis, median follow-up was 18 months (range, 6-55 months). Eleven patients (5.6%) experienced disease relapse, 2 (1%) died of disease, and 3 (1.5%) died of cardiovascular disease. CONCLUSIONS: This study demonstrates the feasibility, safety, and good short-term outcomes of RS in elderly and very elderly gynecologic cancer patients. No patient can be considered too old for a minimally invasive robotic approach, but a multidisciplinary approach is the best management pathway; efforts to reduce associated morbidity are essential.

Can We Define the Risk of Lymph Node Metastasis in Early-Stage Cervical Cancer Patients? A Large-Scale, Retrospective Study.

BACKGROUND: Sentinel lymph node (SLN) biopsy has emerged as one of the most appreciated techniques for reducing the rate of complete lymph node dissection (LND) performed in patients with early-stage cervical cancer (ECC). However, its performances are still a matter of debate and, to improve them, international guidelines recommend performing at least unilateral LND in case of SLN mapping. In a prior study, we identified a group of patients without evidence of lymph node metastasis (LNM). Our objective is to define a precise risk of LNM for each ECC patient in order to significantly tailor surgery for ECC. METHODS: Clinical and pathological data of ECC patients were retrospectively collected by eight Italian institutions. Chi-square test or Fisher's exact test along with logistic regression analysis was used to determine the association of each variable between patients with or without LNM. Results of logistic regression have been used as a basis to calculate the probability to harboring LNM. RESULTS: A total of 463 ECC patients were identified. No LNM was detected among the 161 (34.8%) patients who met the criteria and were defined as Very Low Risk. In the other 302 patients, the precise risk of LNM was calculated, and it was <1% in 31 (10.3%) patients. CONCLUSIONS: Defining the precise risk of LNM could lead to proper selection of patients in whom any lymph nodal procedure, including SLN, could be avoided.

The impact of combined nutraceutical supplementation on quality of life and metabolic changes during the menopausal transition: a pilot randomized trial.

PURPOSE: The aim of this study was to assess the efficacy of a combined nutraceutical supplement on symptoms and early metabolic alterations during the menopausal transition. This pilot randomized study was conducted at the service for menopause disorders of the Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy. METHODS: Ninety women in menopausal transition who attended our service with menopausal symptoms were enrolled in the study. Sixty patients, randomly assigned to the treatment group, were prescribed one daily tablet of a combined nutraceutical compound with phytoestrogen substances, vitamins, micronutrients and passion flower herbal medicine for 6 months. Thirty patients did not receive any treatment and comprised the control group. The intensity of perimenopausal symptoms was assessed by the modified Kuppermann Index (KI) at enrollment and at 3 and 6 months of treatment. At baseline and at the end of the study, patients underwent a clinical evaluation, a pelvic ultrasound and analysis of blood samples. RESULTS: In the nutraceutical supplemented group, a significant reduction in menopausal symptoms was demonstrated according to the KI after 3 and 6 months of supplementation (p < 0.01). The within-group analysis of different KI parameters in the treated group showed a significant improvement in hot flushes (p < 0.001), insomnia (p < 0.01), fatigue (p < 0.01) and irritability (p < 0.01). Metabolic parameters did not change significantly in the nutraceutical supplemented group. In the control group, total cholesterol level showed a significant increase (p < 0.05). CONCLUSIONS: Combined nutraceutical supplementation provides an effective and safe solution for early symptoms occurring during menopausal transition.

Minimally invasive interval debulking surgery in ovarian neoplasm (MISSION trial-NCT02324595): a feasibility study.

BACKGROUND: Laparoscopy has acquired an increasing role in the management of ovarian cancer. Laparoscopic cytoreduction could represent a new frontier for selected patients after neoadjuvant chemotherapy (NACT). OBJECTIVE: We sought to assess feasibility and early complication rate of minimally invasive (MI) interval debulking surgery (IDS) in stage III-IV epithelial ovarian cancer (EOC) patients after NACT. STUDY DESIGN: This is a phase II multicentric study in advanced EOC cases with clinical complete response after NACT, according to Gynecologic Cancer Intergroup and Response Evaluation Criteria In Solid Tumors criteria. Institutional review board approval was obtained and all patients signed written informed consent to be included in the protocol. The study was registered in clinicaltrials.gov (NCT02324595) and was named "MISSION" trial. For patients meeting inclusion criteria, surgical procedures started with diagnostic laparoscopy to confirm preoperative findings and assess surgical complexity. MI-IDS included hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, peritonectomy, and bowel resection. Pelvic and/or aortic lymphadenectomy was not considered as standard procedure in these cases. Intraoperative and postoperative outcomes, time to restart chemotherapy, survival rate, and quality of life data were registered. RESULTS: From December 2013 through February 2015, of 184 advanced EOC patients considered eligible for IDS, 52 (28.2%) met inclusion criteria and were enrolled in the study. For 22 (12%) of them, standard laparotomic approach was preferred because of intraoperative surgeon evaluation. Thirty (16.3%) patients received the planned treatment of MI-IDS. Median age was 61 (range 39-81) years and median body mass index was 24 (range 20-31) kg/m(2). Median numbers of NACT cycles was 4 (range 3-7). Median operative time was 285 (range 124-418) minutes and median estimated blood loss was 100 (range 50-200) mL. Surgical procedures included 28 (93.3%) hysterectomy and bilateral salpingo-oophorectomy, 29 (96.6%) omentectomy, 2 (6.6%) appendectomy, 11 (36.6%) regional peritonectomy, and 1 (3.4%) bowel resection. A residual tumor of 0 cm was reached in 29 (96.6%) patients and 0.5 cm in only 1 (3.4%) case. The vast majority of patients were discharged on postoperative day 2 (range 2-3). No early postoperative complications were registered. Median time to restart chemotherapy was 20 (10-30) days and all patients successfully completed the cycles. Histological findings showed 3 (10%) complete response, 9 (30%) microscopic residual disease, and 18 (60%) evidence of macroscopic residual disease. With a median follow-up of 10.5 month, 5 peritoneal and 2 lymph nodal recurrences were observed. Psychometric test revealed moderate discomfort in the vast majority of patients (66.7%). All patients are still alive. CONCLUSION: Invasive-IDS in patients with clinically complete response to NACT seems to be feasible and safe in terms of perioperative outcomes, psycho-oncological impact, and survival rate. The equivalence between MI surgery and laparotomy needs to be confirmed with a longer follow-up and a larger number of patients.

Laparoscopic Radical Hysterectomy After Concomitant Chemoradiation in Locally Advanced Cervical Cancer: A Prospective Phase II Study.

OBJECTIVE: To assess the feasibility of laparoscopic radical surgery in patients with locally advanced cervical cancer (LACC) who receive chemoradiation therapy (CT/RT). DESIGN: Prospective phase II study (Canadian Task Force classification II-1). INTERVENTION: Patients with LACC (FIGO stage IB2-III) were evaluated for accrual at the Gynecologic Oncology Unit of Catholic University, Rome/Campobasso. Neoadjuvant CT/RT included whole-pelvic irradiation (total dose, 45.0-50.4 Gy) combined with cisplatin and 5-fluorouracil. Objective response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Laparoscopic radical hysterectomy (RH) plus pelvic and/or aortic lymphadenectomy was attempted within 6 to 8 weeks after CT/RT. The feasibility of laparoscopic RH, as well as the rate, pattern, and severity of early and late postoperative complications, were analyzed. RESULTS: Between January 2010 and October 2013, a total of 58 patients were enrolled into the study. After CT/RT, 23 patients (39.6%) underwent type B2 RH, 31 (53.4%) underwent type C1 RH, and 4 (6.9%) underwent type C2 RH. Pelvic lymphadenectomy was performed in all cases. Laparoscopic RH was feasible in 55 of 58 cases (feasibility rate, 94.8%). No intraoperative complications were recorded. During the observation period (median, 22 months; range, 5-50 months), there were 28 complications, of which only 21.4% were grade 2 complications and 14.3% were grade 3 complications. As of January 2015, disease recurrence was documented in 4 cases (6.9%). CONCLUSION: Total laparoscopic radical surgery is feasible in patients with LACC receiving preoperative CT/RT, providing perioperative outcomes comparable to those registered in early-stage disease.

Laparoendoscopic single-site surgery (LESS) for treatment of benign adnexal disease: single-center experience over 3-years.

STUDY OBJECTIVE: To describe the effects of laparoendoscopic single-site (LESS) surgery performed over 3 consecutive years to treat adnexal disease and to report patient perioperative outcomes. DESIGN: Retrospective clinical study (Canadian Task Force classification III). SETTING: Tertiary care academic medical center. PATIENTS: Women undergoing LESS because of a benign gynecologic indication, from January 2009 through December 2011. INTERVENTIONS: Women with benign adnexal disease ≤10 cm underwent LESS surgery through a single 1.5- to 2.0-cm umbilical incision. Intraoperative and postoperative outcomes were carefully recorded, including the need for postoperative rescue analgesia. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-five patients were enrolled. Median patient age was 49 years, and median body mass index was 23. Surgical procedures included unilateral or bilateral salpingo-oophorectomy and unilateral or bilateral cyst enucleation. Median operative time was 48 minutes. Pain control was optimal, with an average visual analog score of 4/10. Both patients and surgeons were highly satisfied with the cosmetic result, and the cosmetic visual analog score was 9/10 at discharge and at 30 days after surgery. The number of women who underwent unilateral or bilateral salpingo-oophorectomy increased progressively and significantly yearly over the study period (16 vs 23 vs 40; p = .001). Median operative time for unilateral or bilateral salpingo-oophorectomy increased significantly from 2009 to 2010 and 2011 (34 vs 45 and 44 minutes; p = .001), together with median BMI (23 vs 23 vs 25; p = .04). CONCLUSION: LESS is a desirable surgical approach in patients with simple adnexal disease.

Perioperative outcomes of laparoendoscopic single-site surgery (LESS) versus conventional laparoscopy for adnexal disease: a case--control study.

OBJECTIVE: This study aimed to evaluate the potential advantages of laparoendoscopic single-site surgery (LESS) approach with respect to conventional laparoscopy. METHODS: Thirty LESS patients were matched 2:1 with a previous cohort of 58 patients undergoing conventional laparoscopy for the same type of surgery (controls). RESULTS: Median operative time (38.5 vs 54 minutes; P = .09) and estimated blood loss (20 vs 30 mL; P = .008) were more favorable in patients undergoing LESS treatment compared with those undergoing conventional laparoscopy. Rupture of the cyst was observed in 11 out of 30 cases (36.6%) and 26 of 58 controls (44.8%; P = .46). Median length of stay was 1 day in the cases and 2 in the controls (P = .03). CONCLUSIONS: Decreases in operative time, estimated blood loss, or length of stay should not be considered a benefit attributable to LESS; rather it seems there are no differences between these 2 surgical approaches after an adequate selection of patients.

NLR and BRCA mutational status in patients with high grade serous advanced ovarian cancer.

Laboratory-markers of the systemic inflammatory-response, such as neutrophil/lymphocyte-ratio (NLR) have been studied as prognostic factors in several tumors but in OC-patients their role is still controversial and no data about the possible correlation with the BRCA-status has been ever reported. We consecutively enrolled a series of 397 newly diagnosed high-grade serous-advanced OC-patients. All patients were tested for BRCA-mutational-status and blood-parameters have been collected 48 h before staging-surgery. A significant correlation of NLR with disease distribution (p < 0.005) was found and patients with NLR < 4 underwent primary-debulking-surgery more frequently (p-value 0.001), with a lower surgical-complexity-score (p-value 0.002). Regarding survival-data, patients with NLR < 4 had a significant 7-month increase in mPFS (26 vs 19 months, p = 0.009); focusing on the BRCA-status, among both BRCA-mutated and BRCA-wild type patients, those with lower NLR had a significantly prolonged mPFS compared to patients with NLR > 4 (BRCA-mutated: 35 vs 23 months, p = 0.03; BRCA-wt: 19 vs 16 months, p = 0.05). At multivariate-analysis, independent factors of prolonged PFS were BRCA mutational status, having received complete cytoreduction and NLR < 4. Also, the strongest predictors of longer OS were BRCA-mutational status, having received complete cytoreductive surgery, NLR < 4 and age. NLR is confirmed to be a prognostic marker in OC-patients and it seems unrelated with BRCA-mutational status.

ToleRability of BevacizUmab in elderly Ovarian cancer patients (TURBO study): a case-control study of a real-life experience.

OBJECTIVE: Bevacizumab maintenance following platinum-based chemotherapy is an effective treatment for epithelial ovarian cancer (EOC), both in primary and recurrent disease. Our aim was to identify criteria to select elderly patients who can safely benefit from bevacizumab addition. METHODS: This is a case-control study on patients with primary or recurrent EOC who received platinum-based chemotherapy plus bevacizumab, between January 2015 and December 2016. Patient characteristics, treatment details and adverse events were reviewed and analyzed in 2 settings: younger (<65 years, group 1) and elderly (≥65 years, group 2). A binary logistic model was applied to correlate clinical variables and severe (grade ≥3) toxicity risk. RESULTS: Overall, 283 patients with EOC were included, with 72 (25.4%) older patients compared with 211 (74.6%) younger women. Bevacizumab had been administered to 234 patients (82.7%) as first-line treatment and in 49 (17.3%) with recurrent disease. At diagnosis, elderly patients presented with at least one comorbidity and were taking at least 1 medication in 84.7% and 80.6% of the cases respectively, compared with correspondingly 47.4% and 37.4% in group 1 (p<0.001). Nonetheless, the occurrence of serious (grade ≥3) adverse events did not increase among the older group. Creatinine serum levels >1.1 g/dL, estimated glomerular filtration rate (eGFR) ≤60 mL/min, ≥3 comorbidities were independently associated with a higher severe toxicity. CONCLUSIONS: Elderly patients with EOC can safely be treated with bevacizumab; factors other than age, as higher creatinine serum levels, eGFR and number of comorbidities should be considered to better estimate bevacizumab-related toxicity risk.

New medical approaches in advanced ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer death among women and the most lethal gynecologic malignancy. Most women with advanced epithelial ovarian cancer will experience many episodes of recurrent disease with progressively shorter disease-free intervals. For women whose disease continues to respond to platinum-based drugs, the disease can often be controlled for 5 years or more. Enormous progress has been made in the management of this disease, and new targeted treatments such as antiangiogenic drugs, poly(adenosine diphosphate-ribose) polymerase inhibitors, and immune checkpoint inhibitors offer potential for improved survival. A variety of combination strategies are being evaluated to leverage these agents. The objective of this review is to summarize results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of ovarian cancer with particular attention to Phase III and ongoing trials.

The safety of bevazicumab for the treatment of ovarian cancer.

INTRODUCTION: The safety profile of bevacizumab (BV) remains a challenging issue, in particular its role in fragile OC patients. Areas covered: In this literature review, we have analyzed safety data from Phase III trials evaluating the combination of BV plus standard chemotherapy in advanced or recurrent OC patients. In particular, our review aimed at clarifying the impact of the drug on fragile patients, and the correlation between BV and postoperative complications after cytoreductive surgery. Expert opinion: The addition of BV to standard chemotherapy regimens may cause unexpected side effects such as hypertension or proteinuria in up to 10% of women receiving the drug. BV administration is not associated with increase postoperative complications after cytoreductive surgery. Artero-venous thromboembolism and gastrointestinal perforation/fistula occurring in around 3% of OC patients treated with BV represent life-threatening events always requiring drug suspension. A closer monitoring is required in selected groups of women including: women with inflammatory bowel disease, or uncontrolled hypertension. Age itself is not a major contraindication, but older women should be carefully evaluated prior to start the drug. Finally, BV maintenance therapy should not be prematurely stopped due to minor events, since drug suspension may reduce survival.

Expression of the glioma-associated oncogene homolog 1 (gli1) in advanced serous ovarian cancer is associated with unfavorable overall survival.

Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, glioblastoma, melanoma as well as pancreas, colorectal, and prostate carcinomas. Here we investigated the role of the transcription factor Gli1 in ovarian cancer. To this end, the expression profile of Gli1 was examined in normal ovaries, ovarian tumors, and ovarian cancer cell lines, and the in vitro effects of a specific Hh-pathway blocker, KAAD-cyclopamine, or a specific Gli1 inhibitor (GANT58) on cell proliferation and on Hh target gene expression were also assessed. Results obtained showed that epithelial cells in ovarian cancer tissue express significantly higher levels of nuclear Gli1 than in normal ovarian tissue, where the protein was almost undetectable. In addition, multivariate analysis showed that nuclear Gli1 was independently associated to poor survival in advanced serous ovarian cancer patients (HR = 2.2, 95%CI 1.0-5.1, p = 0.04). In vitro experiments demonstrated Gli1 expression in the three ovarian carcinoma cell lines tested, A2780, SKOV-3 and OVCAR-3. Remarkably, although KAAD-cyclopamine led to decreased cell proliferation, this treatment did not inhibit hedgehog target gene expression in any of the three ovarian cancer cell lines, suggesting that the inhibition of cell proliferation was a nonspecific or toxic effect. In line with these data, no differences on cell proliferation were observed when cell lines were treated with GANT58. Overall, our clinical data support the role of Gli1 as a prognostic marker in advanced serous ovarian cancer and as a possible therapeutic target in this disease. However, our in vitro findings draw attention to the need for selection of appropriate experimental models that accurately represent human tumor for testing future therapies involving Hh pathway inhibitors.

Postoperative pain after conventional laparoscopy and laparoendoscopic single site surgery (LESS) for benign adnexal disease: a randomized trial.

OBJECTIVE: To compare postoperative pain after laparoendoscopic single-site surgery (LESS) approach with conventional multiaccess laparoscopy (LPS). STUDY DESIGN: Prospective randomized trial. SETTING: University hospital. PATIENT(S): Benign adnexal disease. INTERVENTION(S): Postoperative pain was measured by using the visual analog scale (VAS) at 20 minutes, 2 hours, 4 hours, and 8 hours after surgery. The need for postoperative rescue doses of analgesia was also recorded. MAIN OUTCOME MEASURE(S): Pain after surgery. RESULT(S): A total of 60 patients were enrolled. Within 8 hours, patients who underwent conventional LPS complained of statistically significant greater postoperative pain at VAS evaluation than those undergoing LESS, both at rest and after Valsalva maneuver, with a higher need for rescue analgesia. CONCLUSION(S): LESS provides an advantage over conventional multiaccess LPS in terms of postoperative pain and need for rescue analgesia, with similar perioperative outcomes.