Michael Frumovitz

Quality of Life and Sexual Functioning in Cervical Cancer Survivors

PURPOSE To compare quality of life and sexual functioning in cervical cancer survivors treated with either radical hysterectomy and lymph node dissection or radiotherapy. METHODS Women were interviewed at least 5 years after initial treatment for cervical cancer. Eligible women had squamous cell tumors smaller than 6 cm at diagnosis, were currently disease-free, and had either undergone surgery or radiotherapy, but not both. The two treatment groups were then compared using univariate analysis and multivariate linear regression with a control group of age- and race-matched women with no history of cancer. RESULTS One hundred fourteen patients (37 surgery, 37 radiotherapy, 40 controls) were included for analysis. When compared with surgery patients and controls using univariate analysis, radiation patients had significantly poorer scores on standardized questionnaires measuring health-related quality of life (physical and mental health), psychosocial distress and sexual functioning. The disparity in sexual function remained significant in a multivariate analysis. Univariate and multivariate analyses did not show significant differences between radical hysterectomy patients and controls on any of the outcome measures. CONCLUSION Cervical cancer survivors treated with radiotherapy had worse sexual functioning than did those treated with radical hysterectomy and lymph node dissection. In contrast, these data suggest that cervical cancer survivors treated with surgery alone can expect overall quality of life and sexual function not unlike that of peers without a history of cancer.

Patterns of Gene Expression in Different Histotypes of Epithelial Ovarian Cancer Correlate with Those in Normal Fallopian Tube, Endometrium, and Colon

Purpose: Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Experimental Design: Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. Results: When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Conclusion: Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.

Comparison of total laparoscopic and abdominal radical hysterectomy for patients with early-stage cervical cancer.

OBJECTIVE: To compare intraoperative, pathologic, and postoperative outcomes of total laparoscopic radical hysterectomy with abdominal radical hysterectomy and pelvic lymphadenectomy for women with early-stage cervical cancer. METHODS: We reviewed all patients who underwent total laparoscopic radical hysterectomy or abdominal radical hysterectomy and pelvic lymphadenectomy between 2004 and 2006. RESULTS: Fifty-four patients underwent abdominal radical hysterectomy, and 35 underwent total laparoscopic radical hysterectomy. Mean age was 41.8 years, and mean body mass index 28.1. There was no difference in demographic or tumor factors between the two groups. Mean estimated blood loss was 548 mL with abdominal radical hysterectomy compared with 319 mL with total laparoscopic radical hysterectomy (P=.009), and 15% of patients who underwent abdominal radical hysterectomy required a blood transfusion compared with 11% who underwent total laparoscopic radical hysterectomy (P=.62). Mean operative time was 307 minutes for abdominal radical hysterectomy compared with 344 minutes for total laparoscopic radical hysterectomy (P=.03). On pathologic examination, there was no significant difference in the amount of parametrial tissue, vaginal cuff, or negative margins obtained. A mean 19 pelvic nodes were obtained during abdominal radical hysterectomy compared with 14 during total laparoscopic radical hysterectomy (P=.001). The median duration of hospital stay was significantly shorter for total laparoscopic radical hysterectomy (2.0 compared with 5.0 days, P<.001). For abdominal radical hysterectomy, 53% of patients experienced postoperative infectious morbidity compared with 18% for total laparoscopic radical hysterectomy (P=.001). There was no difference in postoperative noninfectious morbidity. There was no difference in return of urinary function. CONCLUSION: Total laparoscopic radical hysterectomy reduces operative blood loss, postoperative infectious morbidity, and postoperative length of stay without sacrificing the size of radical hysterectomy specimen margins; however, total laparoscopic radical hysterectomy is associated with increased operative time. LEVEL OF EVIDENCE: II

A Phase III Randomized Clinical Trial Comparing Laparoscopic or Robotic Radical Hysterectomy with Abdominal Radical Hysterectomy in Patients with Early Stage Cervical Cancer

STUDY OBJECTIVE Cervical cancer is a significant health problem in countries of the developing world. Although case series suggest advantages of total laparoscopic radical hysterectomy (TLRH) compared with total abdominal radical hysterectomy (TARH), no randomized controlled trial is currently available to establish TLRH as the new standard treatment. In this study, TLRH or total robotic radical hysterectomy (TRRH) will be performed without a vaginally assisted portion of the procedure. DESIGN A biphasic randomized controlled trial was designed to test feasibility of recruitment and equivalence in regard to disease-free survival (Canadian Task Force classification I). SETTING Tertiary referral hospital. PATIENTS Patients with histologically confirmed invasive squamous cell carcinoma or adenocarcinoma of the cervix, stage IA1 (with lymphovascular space invasion), IA2, and IB1 are eligible. INTERVENTIONS During the first phase, 100 patients will be randomized (1:1) to receive either TLRH/TRRH or TARH, with the primary end point being the rate of enrollment. During the second phase, recruitment will be extended by another 640 patients in a 1:1 TLRH/TRRH:TARH allocation, to determine equivalence with respect to disease-free survival with 80% power and alpha=0.05. MEASUREMENTS AND MAIN RESULTS Equivalence will be assumed if the difference in disease-free survival does not exceed 7% at 4 years. Secondary outcomes include treatment-related morbidity, costs and cost effectiveness, patterns of recurrence, quality of life, pelvic floor function, feasibility of intraoperative sentinel node sampling, and overall survival. All data from this multicenter study will be entered using online electronic case report forms, allowing real-time assessment of data completeness and patient follow-up. CONCLUSION This prospective trial aims to show the equivalence of a TLRH/TRRH versus TARH approach for patients with early stage cervical cancer following a 2-phase protocol. This trial was developed and designed with the input and approval of the members of the Gynecologic Oncology Committee from the American Association of Gynecologic Laparoscopists.

Generalizability of cancer clinical trial results: Prognostic differences between participants and nonparticipants

The generalizability of clinical trial results is questionable, because fewer than 5% of cancer patients participate. The authors examined the comparability of clinical trial participants and nonparticipants and the potential impact of differences.

Parametrial involvement in radical hysterectomy specimens for women with early-stage cervical cancer

OBJECTIVE: To estimate the incidence of parametrial involvement and to evaluate factors associated with parametrial spread in women with early-stage cervical cancer and to identify a cohort of patients at low risk for parametrial spread who may benefit from less radical surgery. METHODS: We reviewed all patients who underwent radical hysterectomy and pelvic lymphadenectomy for invasive cervical cancer between 1990 and 2006. All women with squamous, adenocarcinoma, or adenosquamous disease, stage IA2–IB1, who underwent completed radical hysterectomy were included in the analysis. Normally distributed continuous variables were compared using Student’s t-test for independent samples to analyze the outcome of positive or negative parametrial involvement. RESULTS: Three hundred fifty patients met the inclusion criteria. Overall, 27 women (7.7%) had parametrial involvement. The majority of specimens with parametrial involvement (52%) had tumor spread through direct microscopic extension. Patients with parametrial involvement were more likely to have a primary tumor size larger than 2 cm (larger than 2 cm: 14%, smaller than 2 cm: 4%, P=.001), higher histologic grade (grade 3: 12%, grades 1 and 2: 3%, P=.01), lymphovascular space invasion (positive: 12%, negative: 3%, P=.002), and metastasis to the pelvic lymph nodes (positive: 31%, negative: 4%, P<.001). One hundred twenty-five women (36%) had squamous, adenocarcinoma, or adenosquamous lesions, all grades, with primary tumor size 2 cm or smaller and no lymphovascular space invasion. In this group of patients, there was no pathologic evidence of parametrial involvement. CONCLUSION: We were able to retrospectively identify a cohort of women with early-stage cervical cancer who were at very low risk for parametrial involvement. If prospective application of these findings confirms our results, less radical surgery—such as simple hysterectomy, simple trachelectomy, or conization—with pelvic lymphadenectomy may be a reasonable therapeutic option for women with primary tumors 2 cm or smaller and no lymphovascular space invasion. LEVEL OF EVIDENCE: III

Laparoscopic extraperitoneal para-aortic lymphadenectomy in locally advanced cervical cancer 1

Failure to detect metastasis to para‐aortic nodes in patients with locally advanced cervical cancer leads to suboptimal treatment. No previous studies have prospectively compared positron emission tomography (PET)/computed tomography (CT) with laparoscopic extraperitoneal staging in the evaluation of para‐aortic lymph nodes.BACKGROUND Failure to detect metastasis to para-aortic nodes in patients with locally advanced cervical cancer leads to suboptimal treatment. No previous studies have prospectively compared positron emission tomography (PET)/computed tomography (CT) with laparoscopic extraperitoneal staging in the evaluation of para-aortic lymph nodes. METHODS Sixty-five patients were enrolled; 60 were available for analysis. Patients with stage IB2-IVA cervical cancer without evidence of para-aortic lymphadenopathy on preoperative CT or magnetic resonance imaging (MRI) were prospectively enrolled. All patients underwent preoperative PET/CT. Laparoscopic extraperitoneal lymphadenectomy was performed from the common iliac vessels to the left renal vein. RESULTS The median age at diagnosis was 48 years (range, 23-84). The median operative time was 140 minutes (range, 89-252). The median blood loss was 22.5 mL (range, 5-150). The median length of hospital stay was 1 day (range, 0-4). The median number of lymph nodes retrieved was 11 (range, 1-39). Fourteen (23%) patients had histopathologically positive para-aortic nodes. Of the 26 patients with negative pelvic and para-aortic nodes on PET/CT, 3 (12%) had histopathologically positive para-aortic nodes. Of the 27 patients with positive pelvic but negative para-aortic nodes on PET/CT, 6 (22%) had histopathologically positive para-aortic nodes. The sensitivity and specificity of PET/CT in detecting positive para-aortic nodes when nodes were negative on CT or MRI were 36% and 96%, respectively. Eleven (18.3%) patients had a treatment modification based on surgical findings. CONCLUSIONS Laparoscopic extraperitoneal para-aortic lymphadenectomy is safe and feasible. Surgical staging of patients with locally advanced cervical cancer should be considered before planned radiation and chemotherapy.

Lymphadenectomy during endometrial cancer staging: Practice patterns among gynecologic oncologists

OBJECTIVES Several controversies surround lymphadenectomy for endometrial cancer; surgical approach, who to stage, and the anatomic borders of the lymphadenectomy. The purpose of this study was to identify practice patterns among gynecologic oncologists when performing a lymph node evaluation during staging for endometrial cancer. METHODS A self-administered survey was sent via email to all SGO members on 3 occasions between 2/09 and 4/09. The survey addressed surgical approach, algorithms used to determine staging, and anatomic landmarks defining lymphadenectomy. RESULTS Four hundred and six members (40%) responded. Eighty-two percent completed fellowship and 14% were fellows. Thirty-four percent finished fellowship in 2000 or later. Eighty-five percent educate fellows/residents in either academic (65%) or private practice settings (20%). For a majority of cases 40% prefer laparotomy, 31% perform robotic surgery, and 29% use laparoscopy. Minimally invasive surgery was associated with university-based practice (p=0.048). Most (53%) never/rarely use frozen section to determine whether or not to perform lymphadenectomy. A majority perform staging on all grade 2 and grade 3 cancers (66% and 90%, respectively). When performing paraaortic lymphadenectomy, 50% of respondents use the IMA as the upper border and 11% take the dissection to the renal vessels. Participants who completed fellowship in 2000 or later were less likely to go to the renal vessels (p=0.002). CONCLUSION Current controversies in surgical staging for endometrial cancer are reflected in the practice patterns among gynecologic oncologists. At this point it is unclear if standardizing surgical practice patterns will improve outcomes for patients with endometrial cancer.

Trends in laparoscopic and robotic surgery among gynecologic oncologists : A survey update

OBJECTIVES To assess the use of traditional and robotic assisted laparoscopy by Society of Gynecologic Oncology (SGO) members and to compare the results with those of our published survey in 2004. METHODS Surveys were mailed to SGO members, and anonymous responses were collected by mail or through a web site. Data were analyzed and compared with those of our previous survey. In addition, we gathered information on the effect of robotic assisted surgery on the management of gynecologic malignancies. RESULTS Three hundred eighty-eight (46%) of 850 SGO members responded to the survey. Three hundred fifty-two (91%) indicated that they performed laparoscopic surgery in their practice (compared with 84% in the 2004 survey). The three most common laparoscopic procedures were laparoscopic hysterectomy and staging for uterine cancer (43%), diagnostic laparoscopy for adnexal masses (39%), and prophylactic bilateral oophorectomy for high-risk women (11%). Although 76% of respondents had received either limited or no laparoscopic training during their fellowship, 78% now believe that maximum or much emphasis should be placed on laparoscopic training (55% in the 2004 survey). Twenty-four percent of respondents indicated that they performed robotic assisted surgery, with 66% indicating that they planned to increase their use of the procedure in the next year. CONCLUSIONS We found an overall increase in the use of and perceived indications for minimally invasive surgery in gynecologic oncology among SGO members. Endometrial cancer staging has become an accepted indication for laparoscopy. In addition, most respondents were planning on increasing their use of robotic assisted surgery in the next year.

Radical hysterectomy: A comparison of surgical approaches after adoption of robotic surgery in gynecologic oncology

OBJECTIVE To compare intra-operative, postoperative and pathologic outcomes of three surgical approaches to radical hysterectomy and bilateral pelvic lymph node dissection over a three year time period during which all three approaches were used. METHODS We reviewed all patients who underwent radical hysterectomy with pelvic lymph node dissection between 1/2007 and 11/2010. Comparison was made between robotic, laparoscopic and open procedures in regard to surgical times, complication rates, and pathologic findings. RESULTS A total of 95 radical hysterectomy procedures were performed during the study period: 30 open (RAH), 31 laparoscopic (LRH) and 34 robotic (RRH). There were no differences in age, body mass index or other demographic factors between the groups. Operative time was significantly shorter in the RAH compared to LRH and RRH (265 vs 338 vs 328min, p=0.002). Estimated blood loss was significantly lower in LRH and RRH compared with RAH (100 vs 100 vs 350mL, p<0.001). Thirteen (24%) of RAH required blood transfusion. Conversion rates were higher in the LRH (16%) compared to RRH (3%) although not significant (p=0.10). Median length of stay was significantly shorter in RRH (1day) vs LRH or RAH (2 vs 4days, p<0.01). Pathologic findings were similar among all groups. CONCLUSION Minimally invasive surgery has made a significant impact on patients undergoing radical hysterectomy including decrease in blood loss and transfusion rates however; operative times were significantly longer compared to open radical hysterectomy. Our findings suggest that the robotic approach may have the added benefit of even shorter length of stay compared to traditional laparoscopy.