Oliver Zivanovic

Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm☆

OBJECTIVE To determine the impact on progression-free survival (PFS) and overall survival (OS) of a programmatic change in surgical approach to advanced epithelial ovarian cancer. METHODS Two groups of patients with stage IIIC and IV ovarian, tubal, and peritoneal carcinoma were compared. Group 1, the control group, consisted of all 168 patients who underwent primary cytoreduction from 1/96 to 12/99. Group 2, the study group, consisted of all 210 patients who underwent primary surgery from 1/01 to 12/04, during which time a more comprehensive debulking of upper abdominal disease was utilized. RESULTS There were no differences between the groups in age, primary site of disease, surgical stage, tumor grade, American Society of Anesthesiologists class, preoperative serum CA-125 and platelet levels, percentage with or amount of ascites, size or location of largest tumor mass, or type of postoperative chemotherapy. Patients in Group 2 vs Group 1 more frequently had extensive upper abdominal procedure(s) (38% vs 0%, respectively; P<0.001) and cytoreduction to residual disease <1 cm (80% vs 46%, respectively; P<0.01). Five-year PFS and OS rates were significantly improved in Group 2. For Group 2 vs Group 1 patients, 5-year PFS rates were 31% vs 14%, respectively (hazard ratio, 0.757; 95% CI, 0.601-0.953; P=0.01]; and 5-year OS rates were 47% vs 35%, respectively (HR, 0.764; 95% CI, 0.592-0.987; P=0.03]. CONCLUSION The incorporation of extensive upper abdominal procedures resulted in increased optimal cytoreduction rates and significantly improved PFS and OS. A paradigm shift toward more complete primary cytoreduction can improve survival for patients with advanced ovarian, tubal, and peritoneal carcinomas.

An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT)

OBJECTIVE The recent EORTC-NCIC randomized trial comparing primary debulking surgery (PDS) to neoadjuvant chemotherapy (NACT) in advanced epithelial ovarian carcinoma (EOC) reported a median progression-free survival (PFS) of 12 months and overall survival (OS) of 30 months for both arms. Due to the equivalent survival and decreased morbidity with NACT, many now consider it the preferred approach. We analyzed the outcomes of patients treated with PDS at our institution during the same time period in which the EORTC-NCIC trial was conducted, using identical inclusion criteria. METHODS We identified all patients undergoing primary treatment for advanced EOC at our institution from 9/98-12/06. Study inclusion and exclusion criteria were identical to those of the EORTC-NCIC trial. Standard statistical tests were used. RESULTS Of 316 eligible patients, 285 (90%) underwent PDS and 31 (10%) received NACT due to extra-abdominal disease, medical comorbidities, and/or advanced age (>85 years). Of the 285 patients who underwent PDS, most had carcinoma of ovarian origin (248, 87%); stage IIIC disease (249, 87%); grade 3 tumors (237, 83%); and serous histology (249, 87%). Optimal cytoreduction (≤1 cm residual) was achieved in 203 patients (71%). Postoperative platinum-based chemotherapy was given to 281 of 285 patients (99%). The median PFS and OS were 17 and 50 months, respectively. CONCLUSION PDS should continue to be the preferred initial management for patients with bulky stages IIIC-IV ovarian carcinoma. NACT should be reserved for those who cannot tolerate PDS and/or for whom optimal cytoreduction is not feasible.

Oncologic outcome of fertility-sparing radical trachelectomy versus radical hysterectomy for stage IB1 cervical carcinoma.

OBJECTIVE To compare the oncologic outcomes of women who underwent a fertility-sparing radical trachelectomy (RT) to those who underwent a radical hysterectomy (RH) for stage IB1 cervical carcinoma. METHODS We performed a case-control study of all patients with stage IB1 cervical carcinoma who underwent a vaginal or abdominal RT between 11/01 and 6/07. The control group consisted of patients with stage IB1 disease who underwent an RH between 11/91 and 6/07 and who would be considered candidates for fertility-sparing surgery. Information was extracted from a prospectively acquired database. Recurrence-free and disease-specific survival (RFS and DSS) were estimated using Kaplan-Meier estimates and compared with the log-rank test where indicated. Multivariate analysis was performed using the Cox regression method. RESULTS Forty stage IB1 patients underwent an RT and 110 patients underwent an RH. There were no statistical differences between the two groups for the following prognostic variables: histology, median number of lymph nodes removed, node positive rate, lymph-vascular space involvement (LVSI), or deep stromal invasion (DSI). The median follow-up for the entire group was 44 months. The 5-year RFS rate was 96% (for the RT group compared to 86% for the RH group (P=NS). On multivariate analysis in this group of stage IB1 lesions, tumor size <2 cm was not an independent predictor of outcome, but both LVSI and DSI retained independent predictive value (P=0.033 and 0.005, respectively). CONCLUSION For selected patients with stage IB1 cervical cancer, fertility-sparing radical trachelectomy appears to have a similar oncologic outcome to radical hysterectomy. LVSI and DSI appear to be more valuable predictors of outcome than tumor diameter in this subgroup of patients.

The rate of port-site metastases after 2251 laparoscopic procedures in women with underlying malignant disease.

BACKGROUND The aim was to describe the rate of laparoscopic trocar-related subcutaneous tumor implants in women with underlying malignant disease. METHODS An analysis of a prospective database of all patients undergoing transperitoneal laparoscopic procedures for malignant conditions performed by the gynecologic oncology service. RESULTS Between July 1991 and April 2007, laparoscopic procedures were performed in 1694 patients with a malignant intraabdominal condition and in 505 breast cancer patients undergoing risk-reducing, diagnostic or therapeutic laparoscopic procedures without intraabdominal disease. Port-site metastases were documented in 20 of 1694 patients (1.18%) who underwent laparoscopic procedures for a malignant intraabdominal condition. Of these, 15 patients had a diagnosis of epithelial ovarian or fallopian tube carcinoma, 2 had breast cancer, 2 had cervical cancer, and 1 had uterine cancer. Nineteen of 20 patients (95%) had simultaneous carcinomatosis or metastases to other sites at the time of port-site metastasis. Patients who developed port-site metastases within 7 months from the laparoscopic procedure had a median survival of 12 months whereas patients who developed port-site metastasis >7 months had a median survival of 37 months (P=0.004). No port-site recurrence was documented in patients undergoing risk-reducing, diagnostic or therapeutic laparoscopic procedures for breast cancer without intraabdominal disease. CONCLUSION The rate of port-site tumor implantation after laparoscopic procedures in women with malignant disease is low and almost always occurs in the setting of synchronous, advanced intraabdominal or distant metastatic disease. The presence of port-site implantation is a surrogate for advanced disease and should not be used as an argument against laparoscopic surgery in gynecologic malignancies.

Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus.

BackgroundEndocervical adenocarcinomas of the usual type are etiologically related to infection with oncogenic human papillomaviruses (HPVs). These tumors are typically diffusely positive for p16 and carcinoembryonic antigen (CEA) immunostains. The goal of our study was to determine the HPV status and immunohistochemical profiles of unusual histologic subtypes of endocervical adenocarcinoma. MethodsThe study consisted of a total of 26 cases of unusual subtypes including clear cell carcinoma (CCC, n=9), gastric-type adenocarcinoma (GAS, n=11), minimal deviation adenocarcinoma (MDA, n=3), mesonephric adenocarcinoma (MSN, n=1), serous adenocarcinoma (SER, n=1), and malignant mixed Müllerian tumor (n=1). In addition, 5 cases of usual-type endocervical adenocarcinoma (UEA) were included in the study as a control group. The cases were tested for HPV using SPF-10 PCR and LiPA assays, and immunostained for p16, HIK1083, hepatocyte nuclear factor 1-&bgr;, p53, CEA, estrogen receptor (ER), and progesterone receptor (PR). ResultsHPV DNA was not detected in any of the unusual adenocarcinoma subtypes, with the exception of a single case of SER in which HPV16 was detected. p16 positivity did not correlate with HPV status, as 42% of HPV-negative tumors showed patchy/diffuse p16 overexpression; however, p16 positivity was uncommon in GAS/MDA. HIK1083 positivity was limited to GAS and MDA, indicating relative specificity for tumors with gastric mucin expression. Hepatocyte nuclear factor 1-&bgr; was positive in the majority of CCCs and also in other tumor variants and in some UEA as well, indicating a lack of specificity for clear cell differentiation. CEA was consistently negative in CCCs and in a single MSN, but positive in GAS, MDA, SER, and UEA, suggesting that it may serve as a negative marker of clear cell differentiation. p53 was diffusely positive in almost half of the GAS cases, whereas UEA showed mostly negative staining and other variants showed focal staining. PR was negative in all variant cases and in all UEA. ER expression, although mostly negative, showed focal staining in a few variant cases and UEA. ConclusionsUnusual variants of endocervical adenocarcinoma are not related to HPV infection, with only rare exceptions, and p16 overexpression in non-UEA does not correlate with HPV status. Negative staining for PR and ER may serve as a general marker of endocervical neoplasia. GAS/MDA may be differentiated from all other adenocarcinomas with either positive HIK1083 stain or negative/focal p16 stain. Positive CEA stain differentiates GAS/MDA from CCC and negative PR and ER stains differentiate GAS/MDA from benign endocervical glands. CCC may be distinguished from all other adenocarcinomas, except MSN, with a negative CEA stain. Strong and diffuse p53 positivity in SER may be useful in differentiation from UEA. MSN may be identified with negative CEA, ER, and PR stains.

Stage-Specific Outcomes of Patients With Uterine Leiomyosarcoma: A Comparison of the International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems

PURPOSE Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation. RESULTS Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices. CONCLUSION Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.

The incidence of major complications after the performance of extensive upper abdominal surgical procedures during primary cytoreduction of advanced ovarian, tubal, and peritoneal carcinomas.

OBJECTIVE To assess the morbidity and mortality associated with extensive upper abdominal surgery (EUAS) performed during primary cytoreduction for advanced ovarian carcinoma. METHODS We identified all patients who underwent EUAS during primary cytoreduction for advanced ovarian, tubal, or peritoneal cancer at our institution from 1/01 to 12/06. Major grade 3-5 complications were those that led to invasive radiologic intervention, re-operation, unplanned ICU admission, chronic disability, or death within 30 days of surgery. RESULTS There were 141 eligible patients, with a median age of 60 years (range, 38-82). The majority of patients had stage IIIC disease, 103 (73%); serous histology, 131 (93%); and ascites, 118 (84%). There were 229 EUAS procedures performed-diaphragm peritonectomy, 101 (72%); splenectomy, 45 (32%); full-thickness diaphragm resection, 19 (14%); partial hepatectomy, 18 (13%); distal pancreatectomy, 17 (12%); cholecystectomy, 15 (11%); and resection of porta hepatis tumor, 14 (10%). Cytoreductive outcomes were: no gross residual, 42 (30%); residual ≤ 1cm, 85 (60%); and residual >1cm, 14 (10%). Grade 3-5 complications occurred in 31 (22%) patients, including 2 mortalities (1.4%). In 21/31 (68%), the complication was successfully managed with percutaneous drainage of infected or non-infected collections. Overall median survival for all patients was 57 months. CONCLUSIONS Rates of major morbidity and mortality following EUAS for primary cytoreduction were 22% and 1.4%, respectively. Approximately two-thirds of complications were readily managed by percutaneous drainage of collections. With an overall median survival of 57 months in a cohort of patients with a large tumor burden, this rate of morbidity and mortality appears acceptable.

Small cell neuroendocrine carcinoma of the cervix : Analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy

OBJECTIVES To analyze progression-free (PFS) and overall survival (OS) in patients with small cell neuroendocrine carcinoma of the cervix (SCNEC), and to determine whether platinum-based combination chemotherapy is beneficial for this population. METHODS We performed a retrospective analysis of all patients with SCNEC who were treated at our institution between 1/1990 and 2/2007. Patients were excluded if pathologic diagnosis was not confirmed at our institution. Standard statistical methods were utilized. RESULTS Seventeen patients met inclusion criteria. The estimated 3-year PFS and OS rates for the entire group were 22% and 30%, respectively. Median time to progression was 9.1 months. Extent of disease was the only significant prognostic factor. Median OS for patients with early stage disease (IA1-IB2) was 31.2 months and 6.4 months for patients with advanced stage disease (IIB-IV, P=0.034). In the early-stage disease group, the 3-year distant recurrence-free survival rate was 83% for patients who received chemotherapy and 0% for patients who did not receive chemotherapy as part of their initial treatment (P=0.025). The estimated 3-year OS rate was 83% for patients who received and 20% for patients who did not receive chemotherapy as part of their initial treatment (P=0.36). CONCLUSION Given the rarity of SCNEC this retrospective analysis is limited by a small number of patients. However, the natural history of this rare disease is akin to small cell lung cancer and the prognosis is poor due to the tumors propensity for distant spread. The treatment should conform to the treatment of small cell lung cancer.

A contemporary analysis of the ability of preoperative serum CA-125 to predict primary cytoreductive outcome in patients with advanced ovarian, tubal and peritoneal carcinoma

OBJECTIVE We previously reported that preoperative CA-125 may predict primary cytoreductive outcome in patients with stage III ovarian carcinoma (OC). The objective of this study was to perform a contemporary analysis of the ability of CA-125 to predict cytoreductive outcome in advanced OC since our programmatic change in surgical approach that currently incorporates the utilization of extensive upper abdominal procedures, as needed, to achieve maximal cytoreduction. METHODS We reviewed the records of all patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at our institution between 1/01 and 4/05. RESULTS The study cohort included 277 patients. Primary disease sites were: ovary, 232 (84%); tubal, 9 (3%); and peritoneum, 36 (13%). Stages were: IIIA, 6 (2%); IIIB, 12 (4%); IIIC, 215 (78%); and IV, 44 (16%). Tumor grades were: grade 1, 6 (2%); grade 2, 30 (11%); grade 3, 233 (84%), and undifferentiated, 8 (3%). Cytoreductive outcomes were: no gross residual disease (RD), 68 (25%); <or=1 cm RD, 153 (55%); and >cm RD, 56 (20%). There was no threshold CA-125 level that accurately predicted cytoreductive outcome. However, with CA-125 values >500 U/mL, 50% (57/113) of patients required extensive upper abdominal surgery to achieve RD <or=1 cm, compared to 27% (25/93) for those with CA-125 <500 U/mL (P=0.001). CONCLUSION Following our change in surgical paradigm that the incorporated extensive upper abdominal procedures to attain optimal debulking, preoperative CA-125 did not predict the primary cytoreductive outcome of patients with advanced ovarian, tubal, or peritoneal carcinoma. However, with a preoperative CA-125 >500 U/mL, extensive upper abdominal procedures were necessary in 50% of cases to achieve residual disease <or=1 cm. These data may be useful as part of preoperative surgical counseling and planning.

A nomogram to predict postresection 5-year overall survival for patients with uterine leiomyosarcoma†

The clinical course of patients with uterine leiomyosarcoma (LMS) is difficult to predict with the currently available categorical staging systems of the American Joint Committee on Cancer (AJCC) and the International Federation of Gynecology and Obstetrics (FIGO). The objective of the current study was to develop and validate a novel, clinically relevant, individualized prognostic model for patients with uterine LMS.