Peri-operative and survival outcomes analysis of patients with endometrial cancer managed by three surgical approaches: a long-term Bulgarian experience.

The study aim was to assess the peri-operative, oncologic, and survival outcomes for patients with endometrial cancer (EC) managed by abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or robotic hysterectomy (RH) approaches at premier centers in Bulgaria. We analyzed histologically diagnosed EC cases operated via any of the three surgical methods during 2008-2019. Data analyses included patients and tumor characteristics, peri-operative outcomes, and disease status. We grouped FIGO stages I and II to represent early-stage EC and to investigate their survival. Kaplan-Meier and Cox regression analyses were performed to determine disease-free survival (DFS) and overall survival (OS). Consecutive 917 patients (AH = 466; LH = 60, RH = 391) formed the basis of study analyses. Most of demographics and tumor characteristics of the patients were comparable across the groups except few minor variations (e.g., LH/RH cases were younger, heavier, more stage IA, endometrioid, G1, low-risk group). LH and RH group cases had significantly lower operative time than AH (p < 0.001), shorter hospital length-of-stay (p < 0.001), higher post-operative Hgb (p < 0.001). RH cases had fewer blood transfusions than AH or LH (p < 0.001). Cox multivariate analyses indicate that OS was not influenced by the type of surgical approach. Despite the fact that the DFS in "early-stage" EC is significantly better in AH group than RH, the type of surgery (i.e., AH, LH, or RH) for "all stages" is insignificant factor for DFS. With our long-term experience, minimally invasive surgical approach resulted in superior peri-operative, oncologic, and survival outcomes. Specifically, RH is not only safe in terms of post-operative results, but also for mortality and oncologic rates.

Analysis of abdominal vs. robotic radical hysterectomies for patients with cervical cancer: a Bulgarian experience.

To assess and compare the peri-operative, oncologic, and survival outcomes for women with cervical cancer (CC) treated with abdominal radical hysterectomy (ARH) versus robotic radical hysterectomy (RRH) approaches in Bulgaria. We retrospectively analyzed patients with histologically diagnosed CC operated via ARH or RRH methods during January-2008 to April-2019. The data analyzed include patients and tumor characteristics, peri-operative outcomes, and disease status. Kaplan-Meier method and Cox regression analysis were performed to determine disease-free survival (DFS) and overall survival (OS). There were consecutive 1347 patients (ARH = 1006, RRH = 341), which formed the basis of study analyses. Women in the RRH group had significantly shorter median hospital length-of-stay than ARH cases (7 vs. 11 days, p < 0.001), higher post-operative hemoglobin (116 vs. 108 g/L, p < 0.001), and fewer blood transfusions (7.3% vs. 21.5%, p < 0.001), respectively. The overall incidence of post-operative complications was also lower in the RRH vs. ARH group (2.1% vs. 9.4%, p < 0.001). Median follow-up time for ARH vs. RRH groups was 4.32 vs. 5.24 years, respectively (p < 0.001). Kaplan-Meier analysis demonstrated that the RRH cohort had a significantly higher survival rate compared to the ARH group (CC-specific death 8.5% vs. 16.5% respectively). Mean time to recurrence did not differ significantly in either surgical approach (p = 0.495). Cox multivariate regression showed no significant impact of surgical approach on DFS or OS. No significant difference in DFS or OS between ARH vs. RRH for CC was observed. RRH approach does not lead to inferior oncologic outcomes and is associated with better peri-operative outcomes. In regard to "all stages" of CC, we found robotic surgery safer compared to laparotomy, and thus consider RRH a better surgical treatment option for patients with CC.

Improving quality of life in pancreatic cancer patients following high-intensity focused ultrasound (HIFU) in two European centers.

OBJECTIVES: Pancreatic cancer patients often have a high symptom burden, significantly impairing patients' quality of life (QOL). Nevertheless, there are hardly any reports on the impact of high-intensity focused ultrasound (HIFU) on the QOL of treated patients. For the first time, this study evaluated the effect of HIFU on QOL and compared these results in two European centers. METHODS: Eighty patients with advanced pancreatic cancer underwent HIFU (50 in Germany, 30 in Bulgaria). Clinical assessment included evaluation of QOL and symptoms using the EORTC QLQ-C30 questionnaire at baseline and 1, 3, and 6 months after HIFU. Pain intensity was additionally evaluated with the numerical rating score (NRS). RESULTS: Compared to baseline, global health significantly improved 3 and 6 months after HIFU treatment (p = 0.02). Functional subscales including physical, emotional, and social functioning were considerably improved at 6 months (p = 0.02, p = 0.01, and p = 0.01, respectively) as were leading symptom pain (p = 0.04 at 6 months), fatigue (p = 0.03 at 3 and p = 0.01 at 6 months), and appetite loss (p = 0.01 at 6 months). Moreover, pain intensity measured by NRS revealed effective and strong pain relief at all time points (p < 0.001). Reported effects were independent of tumor stage, metastatic status, and country of treatment. CONCLUSIONS: This study showed that HIFU represents an effective treatment option of advanced pancreatic cancer improving QOL by increasing global health and mitigation of physical complaints with a low rate of side effects, independent of the examiner. Therefore, HIFU is a worthwhile additional treatment besides systemic palliative chemotherapy or best supportive care in management of this aggressive disease. KEY POINTS: • In a prospective two-center study, it was shown that HIFU represents an effective treatment option of advanced pancreatic cancer improving QOL. • HIFU in pancreatic cancer patients is associated with a low rate of side effects, independent of the performer. • HIFU is a worthwhile additional treatment besides systemic palliative chemotherapy or best supportive care in management of this aggressive disease.

Efficacy and safety of AEZS-108 (INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the ago-study group (AGO GYN 5).

OBJECTIVES: To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors. METHODS: Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267mg/m(2) equimolar to 76.8mg/m(2) of free doxorubicin) every 3weeks as a two hour i.v. infusion. RESULTS: Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12weeks (95% CI: 8-20weeks), and median overall survival was 53weeks (95% CI: 39-73weeks). Toxicity profile was favorable. CONCLUSION: AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.

Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5).

OBJECTIVE: Advanced or recurrent endometrial cancer (EC) no longer amenable to surgery or radiotherapy is a life-threatening disease with limited therapeutic options left. Eighty percent of ECs express receptors for luteinizing hormone-releasing hormone (LHRH), which can be targeted by AEZS-108 (zoptarelin doxorubicin acetate). This phase 2 trial was performed to assess the efficacy and safety of AEZS-108 in this group of patients. METHODS: Patients had FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) III or IV or recurrent EC, LHRH receptor-positive tumor status, and at least had 1 measurable lesion (Response Evaluation Criteria in Solid Tumors). Prior anthracycline therapy was not allowed. Patients received AEZS-108 as a 2-hour infusion on day 1 of a 21-day cycle. The treatment was continued for a maximum of 6 to 8 cycles. The primary end point was the response rate determined by the Response Evaluation Criteria in Solid Tumors. RESULTS: From April 2008 to November 2009, 44 patients were included in the study at 8 centers in Germany (AGO) and 3 centers in Bulgaria. Forty-three of these patients were eligible. Two (5%) patients had a complete remission, and 8 (18%) achieved a partial remission. Stable disease for at least 6 weeks was observed in 44%. The median time to progression was 7 months, and the median overall survival was 15 months. The most frequently reported grade 3 or 4 adverse effects were neutropenia (12%) and leucopenia (9%). CONCLUSIONS: AEZS-108, an LHRH-agonist coupled to doxorubicin, has significant activity and low toxicity in women with advanced or recurrent LHRH receptor-positive EC, supporting the principle of receptor-mediated targeted chemotherapy.

Robotic-assisted radical parametrectomy in patients with malignant gynecological tumors.

We describe the operative technique of robotic-assisted laparoscopic radical parametrectomy and analyze perioperative data including adequacy of resections, pathology, and complications in our initial cases. A retrospective study was performed of seven patients with gynecological cancers involving the cervix who had previously been treated with simple hysterectomies and then underwent robotic-assisted radical parametrectomies. Pathology from the initial hysterectomies and the radical parametrectomies was reviewed. Postoperative complications, operative times, estimated blood loss, and length of hospital stay were assessed. The upper part of the vagina, parametrial tissue, and bilateral pelvic lymph nodes of all seven patients who had undergone a previous simple hysterectomy were removed. The mean age was 56.4 (SD ± 10.7) years. Diagnoses from hysterectomy specimens were invasive squamous carcinoma (n = 4), endometrial adenocarcinoma (n = 2), and clear-cell papillary adenocystic cervical carcinoma (n = 1). The median number of lymph nodes removed was 8 (min 4, max 29), and one patient had nodal metastasis. The mean operative time was 228.6 (SD ± 38.9) min, estimated blood loss was 147 (SD ± 58.2) ml, and length of hospital stay was five (SD ± 2.3) days. One intraoperative complication (cystotomy) occurred and was successfully repaired. One postoperative fistula developed on postoperative day 10. This early experience demonstrates that the basic surgical and anatomical principles of radical parametrectomy can be applied to robotic-assisted laparoscopic surgery. Genitourinary fistulae are always a concern with this procedure, and minimization of electrocautery near the bladder and ureters may further reduce complications.

Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors.

OBJECTIVES: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS-108 (previously AN-152) consists of [D-Lys6]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects. METHODS: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors. RESULTS: One patient each received intravenous doses of 10, 20, 40, or 80 mg/m² of AEZS-108, six received 160 mg/m² and seven 267 mg/m² at 3 week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS-108. The half-life of AESZ-108 was estimated to be about 2h. CONCLUSIONS: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267 mg/m² and this dose is recommended as starting dose for therapeutic Phase II studies.