Building a Personalized Medicine Infrastructure for Gynecological Oncology Patients in a High-Volume Hospital.

Gynecological cancers require complex intervention since patients have specific needs to be addressed. Centralization to high-volume centers improves the oncological outcomes of patients with gynecological cancers. Research in gynecological oncology is increasing thanks to modern technologies, from the comprehensive molecular characterization of tumors and individual pathophenotypes. Ongoing studies are focusing on personalizing therapies by integrating information across genomics, proteomics, and metabolomics with the genetic makeup and immune system of the patient. Hence, several challenges must be faced to provide holistic benefit to the patient. Personalized approaches should also recognize the unmet needs of each patient to successfully deliver the promise of personalized care, in a multidisciplinary effort. This may provide the greatest opportunity to improve patients' outcomes. Starting from a narrative review on gynecological oncology patients' needs, this article focuses on the experience of building a research and care infrastructure for personalized patient management.

Personalizing vulvar cancer workflow in COVID-19 era: a proposal from Vul.Can MDT.

INTRODUCTION: Since the community spread of Coronavirus disease 2019 (COVID-19), the practice of oncologic care at our comprehensive cancer center has changed. Postponing cancer treatment without consideration of its implications could cost more lives than can be saved. In this special situation, we must continue to provide our cancer patients with the highest quality of medical services assuring the safety. This article provides general guidance on supporting curative treatment strategies in vulvar cancer patients. METHODS: At our institution, a vulvar cancer multidisciplinary team (Vul.Can MDT) of specialists is responsible for personalized treatment of this disease. The phase 2 period necessarily requires specific procedures for both outpatient and inpatient pathways and to provide strategies concerning the management of vulvar cancer patients even in case of an eventually concomitant SARS-CoV-2 infection. In brief, an accurate remote and in person triage must be provided routinely and patients submitted to specific diagnostic tests prior to every major treatment or procedure (surgery, RT, and CT) or in case of suspicion for COVID-19 syndrome. The decisional workflow for these women often old and frail, have been rapidly adjusted by our Vul.Can MDT to mitigate the potential risks of COVID-19. RESULTS: The team produced two types of recommendations concerning: (1) safety regulations of care pathways, patients and health care providers, (2) personalized treatment strategies. We present a protocol that can be applied in clinical practice: the flowcharts provided, include the modulation of treatment intensity designed for surgical procedures and radiation, stratified for FIGO stage of disease and intention. CONCLUSION: We suggest that our proposals are applicable in this setting of patients, considering anyway current international recommendations and guidelines.

Prognostic factors value of germline and somatic brca in patients undergoing surgery for recurrent ovarian cancer with liver metastases.

OBJECTIVE: To describe accurately the oncological outcomes after hepatic resection (HR) in recurrent ovarian carcinoma (ROC) evaluating clinic-pathological variables and mutational status of BRCA1/2. Although HR is considered a challenging situation in ROC patients, assessment of BRCA1/2 mutational status seems to have a relevant clinical value to guide surgical therapy. METHODS: Patients who underwent HR for ROC at the Catholic University of Rome, between June 2012 and October 2017 were included. Exclusion criteria were represented by extra-abdominal disease and presence of diffuse peritoneal carcinomatosis requiring more than 2 bowel resections. Details relative to HR were collected and BRCA analysis was performed. Predictive factors of post-HR progression free survival (PHR-PFS) were assessed by univariate analyses using Cox-proportional hazard regression models. RESULTS: Thirty-four patients undewent HR within secondary cytoreductive surgery (SCS). Six patients (17.6%) presented with hepatic relapse only, while the remaining 28 patients (82.4%) had concomitant extra-hepatic disease. In the whole series, the 3-yr PHR-PFS was 49.1% and the 3-yr post-HR overall survival was 72.9%. Univariate analysis of variables conditioning PHR-PFS showed that only BRCA mutational status played a statistically significant favourable role: the 3-yr PHR-PFS rate was 81.0% in BRCA mutated patient compared to 15.2% in wild type ones (p value: 0.001). CONCLUSIONS: Our clinical analyses suggest that in ROC patients with liver disease the assessment of germline and somatic BRCA mutational status can help to select patients elegible for SCS.

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

OBJECTIVE: Evidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS). METHODS: Cisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit. RESULTS: Nine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 µg/mL vs. Cmax=4.057 µg/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 µg/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054). CONCLUSIONS: We demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01539785.

Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancies using new hybrid CO2 system: preliminary experience in referral center.

The most frequent peritoneal surface malignancies originate principally by gastric cancer, colorectal cancer and ovarian cancer. Apart from the origin, peritoneal carcinosis (PC) is considered a negative prognostic factor. The hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal malignancies is considered an attractive method to deliver chemotherapy with enhanced effect directly at the tumor site. The use of such loco-regional approach has proved to improve prognosis of peritoneal carcinomatosis from different origins. Recently, new devices are suitable for loco-regional intraperitoneal chemotherapy as Peritoneal Recirculation System (PRS-1.0 Combat) with CO2 technology. This is a retrospective study with the aim to assess the perioperative outcomes using PRS. Seventeen patients were enrolled affected by colorectal or ovarian cancer. Complete cytoreduction (RT = 0) was achieved for all cases. Median operative time was 420 min (range: 335-665) and median drugs dose used for HIPEC was 137 mg/m2 (115-756). Median EBL was 200 ml (range 50-1000). Median post-operative hospital stay was 9 days (range: 4-24). Treatment-related early complications were recorded in 8 (47.0%) cases and were G1-G2 Major complications occurred in two (11.7%) cases. Considering our aim to test the PRS in different cases and in different pathologies, the results confirmed that the technique is feasible with good perioperative outcomes.

Cytoreductive surgery followed by HIPEC repetition for secondary ovarian cancer recurrence.

Secondary and tertiary cytoreductive surgery was associated with improved overall survival in platinum-sensitive recurrent ovarian cancer (ROC). Hyperthermic intraoperative intra-peritoneal chemotherapy (HIPEC) is considered an attractive method in the treatment of ROC to deliver chemotherapy with enhanced effect directly at the tumor site. However, another deserving aspect is the feasibility and the oncologic role of HIPEC repetition. Twelve patients affected by secondary ovarian cancer recurrence previously submitted to cytoreduction followed by HIPEC were enrolled for the present study to receive tertiary cytoreduction followed by HIPEC repetition. The median operative time, including time for HIPEC procedure, was 360 min (range 240-540). Average EBL was 325 ml (from 100 to 500 ml). The median hospital stay was of 5 days, from 4 to 10. Low-grade post operatory complications occurred in 2 patients (16.6%) and high-grade complication in 1 case (8.3%). Our study report encouraging data about safety of HIPEC repetition in ovarian cancer treatment.

Upfront HIPEC and bevacizumab-containing adjuvant chemotherapy in advanced epithelial ovarian cancer.

INTRODUCTION: In advanced epithelial ovarian cancer patients, the standard of care is primary debulking surgery, followed by first-line chemotherapy often with bevacizumab addiction. In this context, some experiences have shown that a comprehensive treatment approach to surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis. OBJECTIVE: This is a study aimed to explore the feasibility of primary debulking surgery and HIPEC upfront followed by first-line therapy with bevacizumab. STUDY DESIGN: Phase II monocentric, open label, non-randomised and single-arm study. Forty patients affected by advanced ovarian cancer submitted to primary debulking surgery with HIPEC were enrolled in the study. After surgery, all patients underwent systemic chemotherapy with bevacizumab addiction. RESULTS: Complete cytoreduction (RT = 0) was achieved in all cases. Treatment-related early complications were observed in 23 patients and in 15 cases were G1-G2. Major complications were reported in 8 patients. No postoperative death was recorded. Subsequent chemotherapy was administered in all cases. Median time between surgery and first cycle of chemotherapy was 42 days (range 30-76). Concomitant bevacizumab was administered in 34 patients (85%). Maintenance with bevacizumab was feasible in 33 patients (82.5%) and its withdrawal was necessary for 1 patient (2.5%) due to G3 hypertension. CONCLUSION: Our data suggest that HIPEC can be safely introduced in the upfront therapy of advanced ovarian cancer.

A novel HIPEC technique using hybrid CO2 recirculation system: intra-abdominal diffusion test in a porcine model.

The role of loco-regional treatment of peritoneal carcinomatosis using intraperitoneal chemotherapy is still investigated. Actually, new technologies are suitable for these procedures, especially a new hybrid system using CO2 called Peritoneal Recirculation System (PRS-1.0 Combat). A HIPEC procedure in a porcine model using the PRS system was conducted. The objective of experimentation was to assess the distribution of liquid inside the abdomen, by using methylene blue instead of chemotherapy. Moreover, we positioned six different thermal probes in different abdominal regions inside the abdomen to measure the temperature during procedure. During the procedure, all thermal probes recorded an average temperature of 41.5°. At the end of infusion, the abdomen was emptied and then opened; the tracer distribution was recorded. No technical problems were recorded during the procedure. Good distribution of tracer was recorded. More studies are needed to investigate better this new technology.

1st Evidence-based Italian consensus conference on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinosis from ovarian cancer.

Ovarian cancer (OC) remains relatively rare, although it is among the top 4 causes of cancer death for women younger than 50. The aggressive nature of the disease and its often late diagnosis with peritoneal involvement have an impact on prognosis. The current scientific literature presents ambiguous or uncertain indications for management of peritoneal carcinosis (PC) from OC, both owing to the lack of sufficient scientific data and their heterogeneity or lack of consistency. Therefore, the Italian Society of Surgical Oncology (SICO), the Italian Society of Obstetrics and Gynaecology, the Italian Association of Hospital Obstetricians and Gynaecologists, and the Italian Association of Medical Oncology conducted a multidisciplinary consensus conference (CC) on management of advanced OC presenting with PC during the SICO annual meeting in Naples, Italy, on September 10-11, 2015. An expert committee developed questions on diagnosis and staging work-up, indications, and procedural aspects for peritonectomy, systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy for PC from OC. These questions were provided to 6 invited speakers who answered with an evidence-based report. Each report was submitted to a jury panel, representative of Italian experts in the fields of surgical oncology, gynecology, and medical oncology. The jury panel revised the reports before and after the open discussion during the CC. This article is the final document containing the clinical evidence reports and statements, revised and approved by all the authors before submission.

Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.

Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF small interfering RNA (siRNA) treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia-resistant cancers.

Minimally invasive secondary cytoreduction plus HIPEC versus open surgery plus HIPEC in isolated relapse from ovarian cancer: a retrospective cohort study on perioperative outcomes.

STUDY OBJECTIVE: To compare the perioperative outcomes of minimally invasive secondary cytoreduction surgery (SCS) plus hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) versus open surgery plus HIPEC in a group of platinum-sensitive patients with advanced epithelial ovarian cancer (AEOC) with isolated relapse. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy. PATIENTS: We selected 22 patients with a peritoneal cancer index value of 2. The laparoscopic group consisted of 11 patients who underwent laparoscopic and/or robotic complete cytoreduction plus HIPEC, whereas the laparotomic group consisted of 11 patients who underwent complete laparotomic cytoreduction plus HIPEC. INTERVENTIONS: The minimally invasive surgery (MIS) group were platinum-sensitive single recurrent ovarian cancer patients who underwent either laparoscopic or robotic complete secondary cytoreduction plus HIPEC, whereas the open group were women with similar clinical characteristics who underwent complete secondary cytoreduction plus HIPEC by laparotomy. MEASUREMENTS AND MAIN RESULTS: The median operative time, calculated from the skin incision to the end of SCS (i.e., excluding HIPEC phase) was 125 min (range 95-150 min) in the MIS group and 295 min (range 180-420) in the open group (p = .001), with a median estimated blood loss of 50 mL (range 50-100) and 500 mL (range 50-1300), respectively (p = .025). The median length of hospital stay was 4 days (range 3-17) in the MIS group and 8.5 days (range 4-30) in the open group (p = .002). No statistically significant differences were registered in terms of intra- and postoperative complications between the 2 groups. CONCLUSION: The minimally invasive approach for SCS plus HIPEC is safe and efficient in terms of toxicity and postoperative outcomes for single isolated relapse. HIPEC should not be considered a major contraindication to a minimally invasive approach.

Completion surgery after concomitant chemoradiation in locally advanced cervical cancer: a comprehensive analysis of pattern of postoperative complications.

BACKGROUND: We provided a comprehensive analysis of rate, pattern, and severity of early and late postoperative complications in a very large, single-institution series of locally advanced cervical cancer (LACC) patients administered CT/RT plus radical surgery (RS). METHODS: A total of 362 consecutive LACC (FIGO stage IB2-IVA) patients were submitted to RS after CT/RT at the Gynecologic Oncology Unit of the Catholic University (Rome/Campobasso). At 4 weeks after CT/RT, patients were evaluated for objective response and triaged to radical hysterectomy and pelvic ± aortic lymphadenectomy. Surgical morbidity was classified according to the Chassagne's grading system. RESULTS: Most cases underwent type III-IV radical hysterectomy (N = 313, 86.5 %); pelvic lymphadenectomy was performed in all patients, while 116 patients (32.1 %) were also submitted to aortic lymphadenectomy. A total of 93 patients (25.7 %) experienced any grade postoperative complications, and 60 (16.6 %) had ≥grade 2 complications; grade 3-4 complications occurred in 21 patients (5.8 %). Of all early postoperative complications (N = 100), 31 (31.0 %) were urinary, 9 (9.0 %) were gastrointestinal, and 45 (45.0 %) were vascular. Of all late complications (N = 31), 20 (64.5 %) were urinary, 7 (22.6 %) gastrointestinal, and 2 (6.4 %) were vascular. Multivariate analysis showed that not complete clinical response to treatment retained an independent, unfavorable association with risk of development of postoperative morbidity, while advanced stage, and aortic lymphadenectomy showed only a borderline value. CONCLUSIONS: Failure to achieve clinical complete response to treatment and, to a lesser extent, more advanced stage, and aortic lymphadenectomy, were associated with a higher risk of developing any grade as well as ≥grade 2 complications.

Chemoradiation with concomitant boosts followed by radical surgery in locally advanced cervical cancer: long-term results of the ROMA-2 prospective phase 2 study.

PURPOSE: This prospective, phase 2 study aimed at assessing the efficacy of accelerated fractionation radiation therapy by concomitant boosts (CBs) associated with chemoradiation therapy (CRT) of the whole pelvis, in improving the rate of pathological complete response (pCR) to treatment in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IVA locally advanced cervical cancer. METHODS AND MATERIALS: Neoadjuvant CRT included conformal irradiation of the whole pelvis with a total dose of 39.6 Gy (1.8 cGy/fraction, 22 fractions), plus additional irradiation of primary tumor and parametria with 10.8 Gy administered with CBs (0.9 cGy/fraction, 12 fractions, every other day). Concomitant chemotherapy included cisplatin (20 mg/m(2), days 1-4 and 26-30 of treatment), and capecitabine (1300 mg/m(2)/daily, orally) during the first 2 and the last 2 weeks of treatment. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 6 to 8 weeks from CRT. Toxicity was recorded according to Radiation Therapy Oncology Group toxicity criteria and Chassagne grading system. Based on the Simon design, 103 cases were required, and the regimen would be considered active if >45 pCR were registered (α error = 0.05; ß error = 0.1). RESULTS: pCR was documented in 51 cases (50.5%), and the regimen was considered active, according to the planned statistical assumptions. At median follow-up of 36 months (range: 7-85 months), the 3-year local failure rate was 7%, whereas the 3-year disease-free and overall survival rates were 73.0% and 86.1%, respectively. Grade 3 leukopenia and neutropenia were reported in only 1 and 2 cases, respectively. Gastrointestinal toxicity was always grade 1 or 2. CONCLUSIONS: Addition of CBs in the accelerated fractionation modality to the whole pelvis chemoradiation followed by radical surgery results in a high rate of pathologically assessed complete response to CRT and a very encouraging local control rate, with acceptable toxicity.

Cytoreductive surgery plus HIPEC in platinum-sensitive recurrent ovarian cancer patients: a case-control study on survival in patients with two year follow-up.

OBJECTIVES: To compare survival data in platinum-sensitive recurrent ovarian cancer patients submitted to secondary cytoreduction (SCR) plus hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) (Cases) and a similar group of women not experiencing HIPEC (Controls). METHODS: Case-control study, matching 30 Cases with 37 Controls, with at least 24 months of follow-up. RESULTS: Groups were comparable for all characteristics, except for a higher proportion of patients with single-nodule relapses is the Controls (19 vs. 6; p=0.011). Median follow-up time was 46 months in the Cases and 36 months in the Controls. Twenty patients (66.6%) experienced secondary recurrence in the Cases and 37 women (100%) in the Controls (p=0.001). Moreover, 7 (23.3%) and 23 (62.2%) patients died of disease in the Cases and Controls respectively (p=0.003). The duration of secondary response was 26 months in the Cases and 15 months in the Controls (p=0.004). CONCLUSIONS: The combination of SCR and HIPEC seems to improve survival rate in patients suffering from platinum-sensitive EOC recurrence with respect to no-HIPEC treatments. This result further supports the need of a randomized trial.

HIPEC in recurrent ovarian cancer patients: morbidity-related treatment and long-term analysis of clinical outcome.

OBJECTIVE: To evaluate morbidity and mortality rates associated with the use of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) after optimal cytoreduction (CRS) in a large single-institutional series of platinum-sensitive recurrent ovarian cancer patients. Moreover, disease free (DFS) and overall survival (OS) of previously studied patients have been assessed after a longer follow-up period. METHOD: From May 2005 to October 2010, recurrent ovarian cancer patients with a platinum-free interval of at least 6 months have been prospectively enrolled in a protocol of CRS plus HIPEC with oxaplatinum (460 mg/m(2)) heated to 41.5 °C for 30 min, followed by 6 cycles of systemic chemotherapy with taxotere 75 mg/m(2) and oxaliplatin 100 mg/m(2). RESULTS: Forty-one patients experienced 43 procedures (CRS+HIPEC). An optimal cytoreduction was achieved in all cases (CC-0 95.3%; CC-1 4.7%). A complication rate of 34.8% was registered, with no case of intraoperative death or within 30 days after surgery. Survival curves have been calculated in a group of 25 patients with a minimum follow-up of 18 months, obtaining a median DFS and OS of 24 (range 6-60) and 38 months (range 18-60), respectively. CONCLUSION: In recurrent platinum-sensitive ovarian cancer patients, the use of CRS plus HIPEC represents a safe treatment, able to significantly influence the survival rates compared to chemotherapy alone or surgery plus standard chemotherapy.