Robert W. Holloway

Robotic-assisted hysterectomy for endometrial cancer compared with traditional laparoscopic and laparotomy approaches: A systematic review

OBJECTIVE: To summarize comparative studies describing clinical outcomes of robotic-assisted surgeries compared with traditional laparoscopic or laparotomy techniques for the treatment of endometrial cancer. DATA SOURCES: Using search words “robotic hysterectomy” and “endometrial cancer,” 22 citations were identified from Medline and PubMed (2005 to February 2010). METHODS OF STUDY SELECTION: We selected English language studies reporting at least 25 robotic cases compared with laparoscopic or laparotomy cases that also addressed surgical technique, complications, and perioperative outcomes. Patients underwent total hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. TABULATION, INTEGRATION, AND RESULTS: Eight eligible comparative studies were identified that included 1,591 patients (robotic=589, laparoscopic=396, and laparotomy=606). Pooled means of the resected aortic lymph nodes for robotic hysterectomy and laparoscopy were 10.3 and 7.8 (P=.15), and robotic hysterectomy and laparotomy were 9.4 and 5.7 (P=.28). Pooled means of pelvic lymph nodes for robotic and laparoscopic hysterectomy were 18.5 and 17.8 (P=.95) and 18.0 compared with 14.5 (P=.11) for robotic hysterectomy compared with laparotomy. Estimated blood loss was reduced in robotic hysterectomy compared with laparotomy (P<.005) and laparoscopy (P=.001). Length of stay was shorter for both robotic and laparoscopic cases compared with laparotomy (P<.01). Operative time for robotic hysterectomy was similar to laparoscopic cases but was greater than laparotomy (P<.005). Conversion to laparotomy for laparoscopic hysterectomy was 9.9% compared with 4.9% for robotic cases (P=.06). Vascular, bowel, and bladder injuries; cuff dehiscence; and thromboembolic complications were similar for each surgical method. Transfusions for robotic hysterectomy compared with laparotomy was 1.7% and 7.2% (P=.06) and robotic hysterectomy compared were laparoscopy was 2.6% and 5.0% (P=.22). CONCLUSION: Perioperative clinical outcomes for robotic and laparoscopic hysterectomy appear similar with the exception of less blood loss for robotic cases and longer operative times for robotic and laparoscopy cases.

Robotic-assisted laparoscopic hysterectomy and lymphadenectomy for endometrial cancer: Analysis of surgical performance.

OBJECTIVES To provide an objective analysis of surgical performance of robotic-assisted laparoscopic hysterectomy (RALH) with lymphadenectomy for endometrial cancer during the learning phase of the procedure and to assess opportunities for improvement. METHODS From July 2006 to March 2008, 100 patients with endometrial cancer underwent RALH with lymphadenectomy using the da Vinci Robotic Surgical System. Data were analyzed for operative time (OT), estimated blood loss (EBL), length of stay (LOS), intra-operative complications, surgical-pathologic factors, and post-operative complications using an intent-to-treat analysis. A comparison of the data on a quartile (Q) basis was performed for the 100 RALH cases and separately for the 65 cases that had a complete pelvic-and-aortic lymphadenectomy (PAL). RESULTS Age and body mass index (BMI) did not change significantly during the study. More grade 3 tumors were treated in the last 50 cases (22% vs. 10%, p<0.05). Stage III tumors were identified in 18.7% cases in Q2-4 and none in Q1 (p<0.05). The number of patients undergoing complete PAL and the number of aortic lymph nodes (LN) removed per case increased each quarter. There were 4 (4%) conversions to laparotomy. Delayed vaginal cuff healing decreased from 16% in Q1 to 0% in Q3-4. No case required blood transfusion. Comparing first 10 cases to the last 10 cases, the total LN counts increased from 15 to 21 nodes, the aortic LN counts increased from 4.7 to 8.0, and the OT decreased from 203 to 160 min. Intra-surgeon analysis revealed an improvement in the total LN yields from first 50 to second 50 cases for each surgeon. CONCLUSIONS Operative times decreased and aortic dissections improved with increasing LN counts during the first 100 cases of RALH. Furthermore, patient safety and improvement in surgical performance was demonstrated.

Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash

OBJECTIVES Determine if cetuximab dose escalation to induce grade 2 rash correlates with anti-tumor activity and if sera-based markers could predict likelihood of response. METHODS Patients with persistent/recurrent ovarian or primary peritoneal carcinoma received an initial dose of cetuximab 400 mg/m(2), then 250 mg/m(2) weekly for two 3-week cycles. Patients who had stable disease (SD) and <grade 2 rash were dose escalated in 75 mg/m(2) increments every 3 weeks until grade 2 rash or to a maximum weekly dose of 400 mg/m(2). Pre- and post-treatment serum samples were evaluated for potential predictive markers of response. RESULTS One of 25 patients achieved partial remission (PR) and 9 patients had SD. The median progression free survival was 2.1 months; the 1-year survival rate was 54.8%. Rash (96%) was the most common drug-related adverse event. At first response assessment, 4 patients remained at 250 mg/m(2); 8 patients were dose-escalated to 325 mg/m(2); of these, 4 ultimately were increased to 400 mg/m(2). Patients with progressive disease (PD) were removed from the study. Ninety-two serologic markers were analyzed from 20 patients to identify markers associated with clinical activity and/or predictive of outcome. Pretreatment levels of twelve markers were significantly elevated in patients exhibiting PD versus SD or PR; however, changes in marker levels during the course of treatment were not significant indicators of response. CONCLUSIONS Single-agent cetuximab showed minimal activity in patients with recurrent ovarian cancer. Patients with elevated levels of 12 serologic markers at baseline were more likely to have earlier disease progression.

Surgical staging of uterine cancer: An analysis of perioperative morbidity

Surgical staging documented extrauterine disease in 27.9% of 168 patients with apparent early-clinical-stage uterine cancer. An analysis of operative time (78 +/- 21 min), blood loss (332 +/- 160 cc), and surgical site infection risks (4.7%) indicated little additional risk of lymphadenectomy. The long-term risk of lymphocyst (1.3%) or lymphedema (0.7%) was small. The histologic information obtained from staging was utilized to rationally guide the need for adjunctive teletherapy. The overall risk of recurrence (median follow-up, 26 months) with surgical Stage I disease was 2.6%.

Robotic-assisted surgery in gynecologic oncology: A Society of Gynecologic Oncology consensus statement: Developed by the Society of Gynecologic Oncology's Clinical Practice Robotics Task Force

The Society of Gynecologic Oncologys (“SGO”) Clinical Practice Committee has developed a series of Clinical Documents designed to improve the overall quality of womens cancer care; reduce the use of unnecessary, ineffective or harmful interventions; as well as facilitate the optimal treatment of patients with a goal to maximize the therapeutic benefit, and minimize the risk of harm, at acceptable cost. In developing clinical documents, SGO follows a rigorous process to assure that any conflicts of interest are disclosed and appropriately addressed and that relationships with manufacturers and other third parties do not influence the development process. More specifically, SGO adheres to the principles adopted by the Council of Medical Specialty Societies (“CMSS”) in developing, adopting and promulgating clinical guidelines and consensus statements. Consistent with CMSS principles, SGO received no funding from any manufacturer to support the development of this Consensus Statement nor any other clinical consensus statement or practice guideline developed and published by SGO. In accordance with CMSS principles, SGO requires that its clinical documents be subject to multiple levels of review beginning with a review by SGOs full Clinical Practice Committee. After review and approval by the Clinical Practice Committee, Consensus Statements are submitted to the SGO Council which is SGOs governing body which reviewed and approved the Consensus Statement for submission to SGOs Journal. None of the members of the SGO Council has a financial or other relationship with Intuitive. In accordance with those principles, each member of the Robotics Clinical Task Forcewhich developed the Consensus Statement executed a detailed disclosure statement prior to participating in the Task Force. There is currently only one manufacturer of robotic gynecology technology, Intuitive Surgical Inc., of Sunnyvale, California (“Intuitive”). Onemember of the thirteenmembers of the Robotics Clinical Task Force has a consulting relationship with Intuitive and receives honoraria from Intuitive for teaching advanced courses at his institution. SGO has received unrestricted educational grants from Intuitive to provide educational support for its annual and winter meetings at approximately

Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: A phase III trial of the AGO OVAR, COGI, GINECO, and GEICO-the MIMOSA study

25,000 a year over 5 years. All content for these educational programs was developed in accordance with ACCME standards. Clinical Documents are intended to be educational devices that provide information that may assist healthcare providers in caring for patients. This Clinical Document is not a rule and should not be construed as establishing a legal standard of care or as encouraging,

Hyperactive EGF receptor, Jaks and Stat3 signaling promote enhanced colony-forming ability, motility and migration of cisplatin-resistant ovarian cancer cells

PURPOSE To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission. PATIENTS AND METHODS Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response. RESULTS Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response. CONCLUSION Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

A multicenter evaluation of adjuvant therapy in women with optimally resected stage IIIC endometrial cancer

We present evidence that the cisplatin-resistant human ovarian cancer lines, A2780S/CP1 (S/CP1), A2780S/CP3 (S/CP3) and A2780S/CP5 (S/CP5), derived by subjecting the sensitive A2780S ovarian cancer line to multiple rounds of cisplatin treatments followed by recovery and are resistant to 1, 3 and 5 μM cisplatin, respectively, have increased colony-forming ability and altered morphology that is consistent with enhanced motility, migration and invasiveness in vitro. The malignant phenotype progresses with increasing resistance and is associated with hyperactive epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (Erk)1/2 and janus kinases (Jaks), aberrant signal transducer and activator of transcription (Stat) 3 activation promoted by EGFR and Jaks, and epithelial-mesenchymal transition (EMT) in vitro. Survivin and FLIP anti-apoptotic factors, vascular endothelial growth factor (VEGF) and matrix metalloproteinase activities are also elevated in the resistant cells. Accordingly, the ectopic expression of constitutively-active Stat3C in the sensitive A2780S cells diminished cisplatin sensitivity. The inhibition of EGFR or Stat3 activity repressed Survivin, VEGF and Vimentin expression and the colony-forming potential, viability, motility and migration of the resistant cells, and sensitized them to cisplatin. Analysis of human ovarian cancer patients’ tumor tissues shows aberrantly-active EGFR and Stat3 that in certain cases correlate with Vimentin over-expression. Intra-peritoneal mouse xenograft studies revealed, compared with the sensitive A2780S line that had low tumor incidence restricted to the ovary, a high tumor incidence for the resistant S/CP3 and S/CP5 lines that formed tumor nodules at several locations on the small intestine and colon, and which responded poorly to cisplatin, but were sensitive to concurrent treatment with cisplatin and EGFR or Stat3 inhibitor. Hyperactive EGFR signaling through Stat3 and the Jak-Stat3 activity together promote ovarian cancer progression to cisplatin resistance and therefore represent targets for preventing the development of cisplatin resistance and the recurrent disease during cisplatin therapy in ovarian cancer.

Emergence of robotic assisted surgery in gynecologic oncology: American perspective

OBJECTIVE To determine if there is an advantage to combination chemotherapy and radiation for optimally resected stage IIIC endometrial cancer (EC). METHODS A multicenter retrospective analysis of patients with EC from 1991 to 2008 was conducted. Inclusion criteria were lymph node assessment and optimally resected disease. Recurrence-free (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS 265 patients with optimally resected stage IIIC EC were identified. Postoperative therapies included radiotherapy in 17% (n=45), chemotherapy in 17% (n=46), and both chemotherapy and radiation in 61% (n=161). Three-year RFS was 56% for chemotherapy alone, compared to 73% for radiation alone, and 73% for combination therapy (p=0.12). Those receiving chemotherapy alone had the worst 3-year OS (78%) compared to either radiotherapy alone (95%) or combination therapy (90%) (p=0.005). After adjustment for stage and grade those treated with chemotherapy alone were at a 2.2 fold increased risk of recurrence (95% CI, 1.2 to 4.2; p=0.02) and 4.0 fold increased risk of death (95% CI, 1.6 to 10.0; p=0.004) compared to those treated with chemotherapy and radiation. In contrast there was no significant difference in RFS [HR=1.0 (95% CI, 0.5 to 2.0; p=0.92)] or OS [HR=1.1 (95% CI, 0.3 to 3.6; p=0.91)] for those treated with radiation alone compared to those treated with chemotherapy and radiation. CONCLUSION Adjuvant therapy with either radiation alone or chemotherapy and radiation was associated with improved outcomes for patients with optimally resected stage IIIC EC compared to those treated with chemotherapy only.

Tolfenamic acid inhibits ovarian cancer cell growth and decreases the expression of c-Met and survivin through suppressing specificity protein transcription factors

OBJECTIVES To discuss the emergence of robotic surgery in gynecologic oncology and describe the growth of robotic surgery in a university medical center and a community based practice. METHODS In addition to the historical evolution of the robotic assisted surgery medicine, a survey of robotic cases was performed on two robotic programs since the inception of the programs. A review of the current literature on the use of the da Vinci robot in gynecologic oncology was also performed. RESULTS The robotic surgery programs at UNC Hospital and Florida Hospital are growing steadily since the inception of the programs in 2005 and 2006, respectively. Since 2005 there have also been numerous publications detailing the effectiveness, safety, and efficiency of the robot. CONCLUSIONS Robotic surgery is gaining acceptance and is rapidly growing as evidenced by an increased number of publications on the topic; these publications demonstrate the safety, efficacy, and improved outcomes compared to open surgery and conventional laparoscopy.