Preoperative Conization and Risk of Recurrence in Patients Undergoing Laparoscopic Radical Hysterectomy for Early Stage Cervical Cancer: A Multicenter Study.

STUDY OBJECTIVE: To investigate the factors associated with poorer oncologic outcomes in patients undergoing laparoscopic radical hysterectomy (LRH) for early stage cervical cancer. DESIGN: Multicenter retrospective study. SETTING: Three gynecologic oncology referral centers. PATIENTS: Patients with International Federation of Gynecology and Obstetrics 2009 stage IA (positive lymphovascular space invasion)-IB1 cervical cancer between January 2006 and June 2018. INTERVENTIONS: LRH (Piver type II-III hysterectomies). Lymph-node dissection was accomplished according to the tumor characteristics. MEASUREMENTS AND MAIN RESULTS: Surgical and oncologic outcomes were analyzed. Overall, 186 patients met the inclusion criteria, 16 (8.6%) experienced a recurrence, and 9 (4.8%) died of the disease (median follow-up period 37.9 months). Surgery-related complications did not influence disease-free survival. All the recurrences (16/16; 100%) occurred in patients with stage IB1 disease (p = .02), and 15 (93.7%) in cases involving tumors ≥2 cm. No association between positive lymph node and recurrence was detected (p =.82). Patients who had a preoperative diagnosis through conization (93; 50%) had a significantly lower rate of recurrence than those who underwent cervical biopsy (93; 50%): 1/93 (1.1%) vs 15/93 (16.1%); p <.001). The subanalysis of patients with International Federation of Gynecology and Obstetrics stage IB1 cervical cancer showed that patients undergoing preoperative conization (vs cervical biopsy) were less likely to experience a recurrence (odds ratio 0.09; 95% confidence interval 0.01-0.55). CONCLUSION: We confirmed that LRH was associated with a recurrence rate similar to that reported in the Laparoscopic Approach to Cervical Cancer trial. Tumor size ≥2 cm represents the most important risk factor influencing disease-free survival. However, we found that preoperative conization plays a potentially protective role in patients with an IB1 tumor.

Survival implication of lymphadenectomy in patients surgically treated for apparent early-stage uterine serous carcinoma.

OBJECTIVE: Uterine serous carcinoma (USC) is a rare highly aggressive disease. In the present study, we aimed to investigate the survival implication of the systematic lymphadenectomy in patients who underwent surgery for apparent early-stage USC. METHODS: Consecutive patients with apparent early-stage USC surgically treated at six Italian referral cancer centers were analyzed. A comparison was made between patients who underwent retroperitoneal staging including at least pelvic lymphadenectomy "LND" vs. those who underwent hysterectomy alone "NO-LND". Baseline, surgical and oncological outcomes were analyzed. Kaplan- Meier curves were calculated for disease-free survival (DFS) and disease-specific survival (DSS). Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). RESULTS: One hundred forty patients were analyzed, 106 LND and 34 NO-LND. NO-LND group (compared to LND group) included older patients (median age, 73 vs.67 years) and with higher comorbidities (median Charlson Comorbidity Index, 6 vs. 5) (p<0.001). No differences in terms of recurrence rate (LND vs. NO-LND, 33.1% vs. 41.4%; p=0.240) were observed. At Cox regression analysis lymphadenectomy did not significantly influence DFS (HR=0.59; 95% confidence interval [CI]=0.32-1.08; p=0.09), and DSS (HR=0.14; 95% CI=0.02-1.21; multivariable analysis p=0.07). Positive node was independently associated with worse DFS (HR=6.22; 95% CI=3.08-12.60; p<0.001) and DSS (HR=5.51; 95% CI=2.31-13.10; p<0.001), while adjuvant chemotherapy was associated with improved DFS (HR=0.38; 95% CI=0.17-0.86; p=0.02) and age was independently associated with worse DSS (HR=1.07; 95% CI=1.02-1.13; p<0.001). CONCLUSIONS: Although lymphadenectomy did not show survival benefits in patients who underwent surgery for apparent early-stage USC, the presence of lymph node metastasis was the main adverse prognostic factors, supporting the prognostic role of the retroperitoneal staging also in this histological subtype.

Communicating BRCA research results to patients enrolled in international clinical trials: lessons learnt from the AGO-OVAR 16 study.

BACKGROUND: The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. METHODS: An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may be beneficial to patients and their families. RESULTS: Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. CONCLUSION: This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. TRIAL REGISTRATION: This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees (Additional file 1).

Chemotherapy reduces para-aortic node recurrences in endometrial cancer with positive pelvic and unknown para-aortic nodes.

OBJECTIVE: The objective of this study was to evaluate how the administration of different adjuvant therapies influences the risk for developing recurrences in the para-aortic area in endometrial cancer (EC) with positive pelvic and unknown para-aortic nodes. METHODS: We retrospectively evaluated the data of 58 patients with EC affected by stage IIIC1 who had undergone pelvic but not para-aortic lymphadenectomy from January 1, 1990 to December 31, 2011. Survival outcomes within the first 5 years after surgery were assessed using the Kaplan-Meier model. RESULTS: Chemotherapy plus radiotherapy, chemotherapy only, and external radiotherapy only were administered in 12 (23%), 18 (34%), and 23 (43%) patients, respectively. Five (9%) patients, who were selected to forego adjuvant therapy due to poor performance status, were excluded from the analysis. Disease-free and overall survivals assessed at 5 years were 54%, and 61%, respectively. All para-aortic recurrences were observed among the patients with endometrioid EC, whereas no cases of para-aortic recurrences were found in patients with nonendometrioid histology (5/36 (14%) vs 0/17 (0%); P = 0.16); the latter were more likely to develop distant (hematogenous, peritoneal, and distant lymphatic) recurrences (P = 0.09). Type of adjuvant therapy was the only factor influencing para-aortic failure: chemotherapy (± radiotherapy) reduced the rate of para-aortic node recurrence in comparison with pelvic radiotherapy as a sole modality (P = 0.01). However, adjuvant therapy did not influence the 5-year survival outcomes (P > 0.05). CONCLUSIONS: In the absence of local treatment (ie, para-aortic lymphadenectomy and radiotherapy), the administration of chemotherapy seems effective in reducing recurrences in the para-aortic area among patients with stage IIIC1 endometrioid EC.

A prospective case-control study on the impact of neoadjuvant chemotherapy on surgery-related outcomes of laparoscopic radical hysterectomy.

AIM: To investigate whether perioperative outcomes of class III/type C laparoscopic radical hysterectomy (LRH) for cervical cancer (CC) are influenced by neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: Data of consecutive patients, affected by locally advanced-stage CC, undergoing NACT plus LRH were matched 1:2 with consecutive patients, affected by early-stage CC who underwent LRH without NACT. RESULTS: Twenty and 40 patients underwent NACT with LRH and LRH aIone, respectively. Demographic characteristics were balanced between groups. Number of lymph nodes yielded, parametrial width and length of vaginal cuff were not influenced by preoperative administration of NACT. Patients undergoing NACT plus LRH experienced slightly higher blood loss (225 vs. 200 ml; p=0.05) than patients in the control group, but had a similar operative time and length of hospital stay. No between-group differences in transfusion and complications rates were observed (p>0.2). CONCLUSION: The administration of NACT does not affect the surgery-related outcomes of LRH.

Predictors of postoperative morbidity after laparoscopic versus open radical hysterectomy plus external beam radiotherapy: a propensity-matched comparison.

BACKGROUND: Identification of peri-operative variables predicting postoperative morbidity may improve postoperative patients' care. We aimed to identify patients' characteristics and operative factors predictive of early (≤ 30-day) and late (≤ 6-month) morbidity in cervical cancer patients undergoing surgery plus external beam radiotherapy (EBRT). METHODS: We studied 45 propensity-matched patient pairs (90 patients) undergoing laparoscopic radical hysterectomy (LRH) plus EBRT vs. abdominal radical hysterectomy (RAH) plus EBRT. Basic descriptive, multivariable and artificial neuronal network analyses (ANN) were used to design predicting models influencing outcomes. RESULTS: Baseline characteristics of the study populations were similar. Patients undergoing LRH experienced lower blood loss (200 (range, 10-700) vs. 400 (range, 100-2000) ml; P < 0.001), shorter length of hospital stay (4 (range, 1-10) vs. 8 (range, 5-52) days; P < 0.001) and similar operative time (235 (± 67.3) vs. 258 (± 70.2) min; P = 0.14) than patients undergoing RAH. We observed that, at multivariate analysis, open approach correlated with overall (OR: 1.2; 95%CI: 1.03-1.46), early (OR: 1.14; 95%CI:0.99-1.3) and late (OR: 1.13; 95%CI: 1.001-1.28) postoperative complications. CONCLUSIONS: Open approach is the main predictor for developing morbidity among cervical cancer patients undergoing radical hysterectomy followed by adjuvant radiotherapy. Laparoscopic surgery enhances peri-operative surgical results and minimizes the occurrence of late complications.

Primary squamous cell carcinoma of the endometrium in elderly women: a report of four cases.

Pure squamous cell carcinoma arising in the endometrium represents a rare entity, accounting for <1 % of all endometrial malignancies. Limited data about pathogenetics' and behaviours' features are available. Of consequence, there is no consensus about classification and different therapeutic option. Four cases of elderly patients (aged > 65 years) affected by pure squamous cell carcinoma of the endometrium are presented. Known risk factors for endometrial squamous metaplasia (i.e., pelvic inflammatory disease and cervical stenosis) were observed in two patients. Patients with a disease limited to the uterine corpus had favourable prognosis after surgery ± radiotherapy, while one patient with lymph nodes involvement and another who refused staging and/or adjuvant therapy had recurrent disease. Primary squamous cell carcinoma of the endometrium is rare and aggressive occurrence, characteristic of elderly patients. Radical surgery and adjuvant radiotherapy should be administered.

Secondary analyses from a randomized clinical trial: age as the key prognostic factor in endometrial carcinoma.

OBJECTIVE: The purpose of this study was to explore in greater depth the outcomes of the Italian randomized trial investigating the role of pelvic lymphadenectomy in clinical early stage endometrial cancer. In the attempt to identify the patients with poorer prognosis, the impact of age and body mass index were also thoroughly investigated by cancer-specific survival (CSS) analyses. STUDY DESIGN: Survival outcomes of trial patients were analyzed in relation to age (≤65 years and >65 years) in the 2 arms (lymphadenectomy and no lymphadenectomy) and in the whole population of the trial. RESULTS: Univariate and multivariable analyses of CSS and overall survival (OS) of patients showed that age >65 years is a strong independent poor prognostic factor (5-y OS 92.1% and 78.4% in ≤65 years and >65 years patients, respectively, P < .0001; 5-y CSS 93.8% and 83.5% in ≤65 years and >65 years patients, respectively, P = .003). Among women ≤65 years, node negative patients had 94.4% 5-y OS and 96.3% 5-y CSS vs 74.3% 5-y OS and 74.3% 5-y CSS for node positive patients (P = .009 and P = .002, respectively), while among women >65 y, node negative patients had 75.7% 5-y OS and 83.6% 5-y CSS vs 74.1% 5-y OS and 83.3% 5-y CSS for node positive patients (P = .55 and P = .58, respectively). Univariate and multivariable survival analyses in the whole trial population showed that older age, and higher tumor grade and stage were significantly associated to a worse prognosis. CONCLUSION: Older women faced an intrinsic poorer survival whether or not they underwent lymphadenectomy, and, unexpectedly, irrespective of the presence of nodal metastasis. Only in older patients was obesity (body mass index >30) significantly associated with scarce prognosis.

Primary mammary-like ductal carcinoma of the vulva: a case report and analysis of the literature.

Mammary-like vulvar carcinoma represents an extremely rare disease. Here, the authors report a case of mammary-like ductal carcinoma of the vulva. A 71-year-old woman affected by stage T2N1M0 mammary-like vulvar carcinoma underwent neoadjuvant chemotherapy, radical vulvectomy, and adjuvant antioestrogen hormone therapy. The patient is alive, 24 months after surgery, with no clinical and radiological evidence of disease. To provide a better insight in to the clinical approach for this rare disease, a review of the available literature was performed.

Primary peritoneal cancer in Lynch syndrome: a clinical-pathologic report of a case and analysis of the literature.

Lynch syndrome is a genetic disease, caused by a germ-line mutation in a mismatch repair gene, related to an increased risk of developing colorectal and extracolonic cancer. Despite that, the incidence of primary peritoneal cancer after adnexectomy remains unknown. We here report a case of primary peritoneal cancer in a woman affected by Lynch syndrome who underwent hysterectomy+salpingo-oophorectomy for endometrial cancer 13 yr before. Morphology and immunophenotype allowed to differentiate peritoneal malignancy from the previously diagnosed endometrial carcinoma. Physicians should be aware of the potential risk of primary peritoneal cancer in women affected by Lynch syndrome, despite previous prophylactic surgery.

Perioperative allogenic blood transfusions and the risk of endometrial cancer recurrence.

PURPOSE: To evaluate the effect of perioperative blood transfusions on the risk of recurrence of endometrial cancer. METHODS: This study is a retrospective analysis of 358 consecutive patients, without a history of other tumors, who underwent surgery for endometrial cancer between January 2000 and April 2010. RESULTS: Women who did not need any transfusion (N = 331) and patients who received allogenic blood donations (N = 27) were compared in terms of risk of cancer recurrence. The surgical standard procedure included peritoneal washing for cytologic examination, total hysterectomy + bilateral adnexectomy (N = 358), and pelvic lymphadenectomy (N = 227). The two groups were homogeneous in term of age, BMI, previous abdominal surgery, type of intervention, operative time, nodal count, and hospital stay. The median (range) estimated blood loss was higher in the transfusion group, 400 mL (100-2,000 mL), than in the non-transfusion group, 150 mL (10-1,000 mL). Median (range) follow-up was 67.5 months (6-132.4 months). Blood transfusions were associated with a higher relapse rate (P = 0.0021). At multivariate analysis, administration of packed red blood cells remained independently associated with recurrence (OR 4.64; CI 95 % 1.45-14.9), as well as myometrial invasion ≥50 % (OR 2.88; CI 95 % 1.18-7.07) and stage >1 (OR 4.24; CI 95 % 1.75-10.3). CONCLUSIONS: The use of allogenic blood transfusions is associated with a higher risk of recurrence. We hypothesize that this could be due to a transitory perioperative immunodepression that promotes the spread of neoplastic cells.

Early decline in cancer antigen 125 as a surrogate for progression-free survival in recurrent ovarian cancer.

We used data from 886 patients from the CAELYX in Platinum Sensitive Ovarian Patients (CALYPSO) trial, recruited between April 2005 and September 2007, to examine the role of early decline in cancer antigen 125 (CA125) and early tumor response as prognostic factors and surrogates for superiority of treatment with carboplatin-pegylated liposomal doxorubicin (CPLD) compared with carboplatin-paclitaxel (CP) in a landmark analysis. Progression-free survival (PFS) was estimated by Kaplan-Meier analyses. We used univariate and multivariable Cox proportional hazards analyses to assess early decline and early response as surrogates for CPLD treatment benefit compared with CP. All statistical tests were two-sided. Early decline (defined as rate of CA125 decrease of at least 50% per month) was associated with improved PFS (adjusted hazard ratio [HR] for progression = 0.81, 95% confidence interval [CI] = 0.67 to 0.97, P = .02) but early response (complete or partial responses) was not. CPLD was associated with improved PFS compared with CP (HR = 0.82, 95% CI = 0.69 to 0.96, P = .01). However, fewer CPLD patients had an early decline (161 [37.4%] vs 233 [51.2%], P < .001) or an early response (146 [33.9%] vs 176 [38.7%], P = .14) compared with CP patients. The PFS for CPLD patients did not change statistically significantly after adjustment for early decline (adjusted HR = 0.80, 95% CI = 0.68 to 0.94, P = .007). These findings are opposite to what would be expected if these markers were good surrogates for treatment benefit.

Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial.

BACKGROUND: Pelvic lymph nodes are the most common site of extrauterine tumor spread in early-stage endometrial cancer, but the clinical impact of lymphadenectomy has not been addressed in randomized studies. We conducted a randomized clinical trial to determine whether the addition of pelvic systematic lymphadenectomy to standard hysterectomy with bilateral salpingo-oophorectomy improves overall and disease-free survival. METHODS: From October 1, 1996, through March 31, 2006, 514 eligible patients with preoperative International Federation of Gynecology and Obstetrics stage I endometrial carcinoma were randomly assigned to undergo pelvic systematic lymphadenectomy (n = 264) or no lymphadenectomy (n = 250). Patients' clinical data, pathological tumor characteristics, and operative and early postoperative data were recorded at discharge from hospital. Late postoperative complications, adjuvant therapy, and follow-up data were collected 6 months after surgery. Survival was analyzed by use of the log-rank test and a Cox multivariable regression analysis. All statistical tests were two-sided. RESULTS: The median number of lymph nodes removed was 30 (interquartile range = 22-42) in the pelvic systematic lymphadenectomy arm and 0 (interquartile range = 0-0) in the no-lymphadenectomy arm (P < .001). Both early and late postoperative complications occurred statistically significantly more frequently in patients who had received pelvic systematic lymphadenectomy (81 patients in the lymphadenectomy arm and 34 patients in the no-lymphadenectomy arm, P = .001). Pelvic systematic lymphadenectomy improved surgical staging as statistically significantly more patients with lymph node metastases were found in the lymphadenectomy arm than in the no-lymphadenectomy arm (13.3% vs 3.2%, difference = 10.1%, 95% confidence interval [CI] = 5.3% to 14.9%, P < .001). At a median follow-up of 49 months, 78 events (ie, recurrence or death) had been observed and 53 patients had died. The unadjusted risks for first event and death were similar between the two arms (hazard ratio [HR] for first event = 1.10, 95% CI = 0.70 to 1.71, P = .68, and HR for death = 1.20, 95% CI = 0.70 to 2.07, P = .50). The 5-year disease-free and overall survival rates in an intention-to-treat analysis were similar between arms (81.0% and 85.9% in the lymphadenectomy arm and 81.7% and 90.0% in the no-lymphadenectomy arm, respectively). CONCLUSION: Although systematic pelvic lymphadenectomy statistically significantly improved surgical staging, it did not improve disease-free or overall survival.

Carcinosarcoma of the uterine cervix: case report and discussion.

BACKGROUND: Cervical carcinosarcomas are rare neoplasms; optimal treatment is unclear. CASE 1: A 42-year-old woman underwent abdominal hysterectomy because of bleeding, anaemia and uterine fibromatosis. Histology showed a homologous carcinosarcoma of the cervix. Laparoscopic re-staging (pelvic lymphadenectomy, bilateral salpingo-oophorectomy) was negative for neoplasia. Adjuvant chemotherapy with ifosfamide and cisplatin was performed. At 48 months of follow-up, the patient is NED. CASE 2: A 74-year-old woman reporting vaginal bleeding, with carcinosarcoma on the cervical biopsy, underwent radical hysterectomy, bilateral salpingo-oophorectomy, pelvic and paraortic lymphadenectomy. Histology confirmed a homologous carcinosarcoma of the cervix, stage IIb. Whole-pelvis irradiation and brachytherapy were carried out. Nine months later, the patient developed systemic recurrence and died of disease. Aggressive primary therapy can result in cure of early-stage cervical carcinosarcomas. Extracervical disease is associated with a poor prognosis.

A comparison of urinary complications following total laparoscopic radical hysterectomy and laparoscopic pelvic lymphadenectomy to open abdominal surgery.

OBJECTIVE: The objective of this study was to compare total laparoscopic radical hysterectomy (TLRH) and laparoscopic pelvic lymphadenectomy (LPS) to total abdominal radical hysterectomy (TARH) and pelvic lymphadenectomy (LPT) in terms of urinary tract lesions and postoperative urinary retention. METHODS: Starting in 2004, we treated all early stage cervical cancer patients with TLRH and LPS. The control group for this analysis was a historical cohort of patients treated with TARH+LPT. Within the TLRH+LPS group, we assessed whether the width of parametrial tissue removed was a risk factor for urinary tract injuries or postoperative urinary retention. RESULTS: Fifty women were included in the TLRH+LPS group and forty-eight were included in the TARH+LPT group. There were no conversions from laparoscopy to laparotomy. There was no statistically significant difference in intraoperative urinary complications between the groups. Four (8%) intraoperative urinary tract injuries in the LPS (3 cystotomies and 1 ureteral lesions all repaired laparoscopically) and 2 (4.2%) in the LPT group (2 cystotomies) occurred (p=0.68). Similarly, there was no statistically significant difference in postoperative urinary complications between groups. Urinary postoperative complications were: 1 (2%) ureterovaginal and 1 vesicovaginal fistulas, 1 delayed ureteric fistula in LPS group vs. 0 in LPT group (p=0.24). Urinary retention was complained by 7 (14%) and 7 (14.6%) patients in LPS and LPT groups respectively (p=1.00). The average width of parametrial tissue removed in the LPS group was 32.2+14.0 mm in patients with vs. 39.5+13.6 mm in patients without urinary complications (p=0.11). CONCLUSIONS: A laparoscopic approach is comparable to the laparotomy in terms of urinary lesions and postoperative retention. The width of parametrium removed does not affect the risk of urinary lesions or postoperative retention.