Long-term survival after fertility-sparing surgery for epithelial ovarian cancer.

OBJECTIVE: To determine the long-term results of fertility-sparing surgery in the treatment of early-stage invasive epithelial ovarian cancer. METHODS: A retrospective review of 123 patients who underwent surgical staging for FIGO stage I epithelial ovarian cancer from November 1982 to July 2002. Demographics, stage, histopathology, adjuvant therapy, recurrence, and survival were compared for patients who had fertility-sparing surgery and for those having standard surgical staging. RESULTS: Twenty patients, with a median age of 27 years, had preservation of the uterus and contralateral ovary at the time of surgical staging. Platinum-based chemotherapy was administered to 50% of these patients postoperatively. Three patients (15%) recurred in the retained ovary at 9, 20, and 22 months, and all died of their disease. One patient was diagnosed with primary endometrial cancer at 15 months and was salvaged with hysterectomy. At a median follow-up of 122 months, 17 (85%) of 20 patients treated with fertility-sparing surgery were alive without disease. Of the 103 patients treated with removal of the uterus and both ovaries, 72% received adjuvant platinum chemotherapy. Twenty (19%) of the patients in the standard surgery group have recurred, and 17 have died of disease. At a median follow-up of 113 months, 78 (76%) of 103 patients treated with standard surgery were alive without disease. Five-year survival data showed no significant difference in the recurrence-free survival of the fertility-sparing and standard surgery groups (84% vs 78%) or overall survival (84% vs 82%). CONCLUSION: Fertility-sparing surgery is a reasonable alternative treatment for young women with stage I epithelial ovarian cancer desiring fertility preservation.

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

PURPOSE: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. EXPERIMENTAL DESIGN: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. RESULTS: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). CONCLUSIONS: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: application toward a dynamic disease state model of ovarian cancer.

PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC. PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories. CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.

The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer.

PURPOSE: Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes. EXPERIMENTAL DESIGN: ZIC2 expression levels were analyzed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints. RESULTS: ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines but undetectable in LMP cell lines. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL, ZIC2 expression was significantly associated with overall survival in both univariate (P = 0.046) and multivariate model (P = 0.049). CONCLUSIONS: ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs.

CA125 level as a predictor of progression-free survival and overall survival in ovarian cancer patients with surgically defined disease status prior to the initiation of intraperitoneal consolidation therapy.

OBJECTIVES: Recent data suggest that differences in CA125 levels within the normal range may predict progression-free survival (PFS), but limited information is available regarding the value of these differences in predicting overall survival (OS) in patients with epithelial ovarian cancer. The objective of this study was to determine whether CA125 is an independent predictor of OS in patients with surgically defined disease status at the end of primary therapy prior to intraperitoneal (IP) consolidation chemotherapy. A secondary objective was to assess the relationship of CA125 level to PFS. METHODS: Using data from a retrospective cohort of 433 patients who received intraperitoneal (IP) therapy following primary treatment for ovarian cancer between 1984 and 1998, we identified 241 patients with a complete clinical response and CA125 data at the time of second-look surgery prior to IP chemotherapy. Patient demographics and updated follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox regression models were used for multivariate analysis. RESULTS: The majority of patients had advanced stage III or IV disease (n=201, 83%) and high-grade histology (n=163, 68%). Taxane was used as part of primary platinum-based therapy in 56% (n=134) of patients, and subsequent IP chemotherapy was platinum-based in 85% (n=206). When considered as a continuous variable, CA125 was a predictor of OS (P=0.029). Using the median CA125 level in our study group as a cut-off, OS was increased in patients with CA125 < or =12 U/ml (median 5.8 years) compared with >12 (3.7 years) (P=0.0027). CA125 level was an independent predictor of OS (HR: 1.410; 95% CI, 1.044, 1.904, P=0.0248) in a multivariate model that included stage (P=0.0166), grade (P=0.0001), and findings at second-look surgery (P=0.0003). CA125 level was also a predictor of clinical PFS (radiographic or CA125 elevation criteria alone) in a subset of 161 patients as a continuous variable (P=0.0036), and when divided at the median (< or = or >12; median 2.8 years vs. 1.7 years; P=0.0017). CONCLUSIONS: In our study population, CA125 level at the end of primary therapy was a predictor of OS and PFS when considered as a continuous variable, or when divided at the median (< or = or >12 U/ml). Further prospective study is required to optimize clinically significant cut-off values within the normal range of CA125 levels for both OS and PFS endpoints.

The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer.

OBJECTIVES: To determine the survival impact of adding extensive upper abdominal surgical cytoreduction to standard surgical techniques for advanced ovarian cancer. METHODS: The records of all patients with stages IIIC-IV epithelial ovarian cancer who underwent primary surgery at our institution from 1998 to 2003 were reviewed. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease

Fifth International Conference on Ovarian Cancer: challenges and opportunities.

OBJECTIVE: This paper provides a summary of the presentations given at the Fifth International Conference on Ovarian Cancer in Houston, Texas on December 1-4, 2004. METHODS AND RESULTS: The focus of this meeting was to discuss the most current information regarding development, progression, diagnosis, and therapy of ovarian cancer. The presentations at this conference were grouped into 7 sessions, and are summarized in this paper as follows: ovarian cancer biology, novel therapeutic approaches, surgical and pathological controversies, quality of life/biobehavioral aspects of ovarian cancer, screening/prevention approaches, management of uncommon ovarian cancers, and treatment controversies. CONCLUSION: While many challenges remain in the overall management of ovarian carcinoma, the speakers at this conference reviewed the opportunities available to scientists and clinicians to work collaboratively to make advances.

Quality of life in women at risk for ovarian cancer who have undergone risk-reducing oophorectomy.

OBJECTIVES: Women at risk for ovarian cancer may consider risk-reducing salpingo-oophorectomy (RRSO), and desire information regarding the health consequences of the procedure. We studied women who had undergone RRSO to assess quality of life after the procedure. METHODS: Women (n = 59) undergoing RRSO between 1 January 1997 and 31 July 2000 completed a questionnaire composed of the Symptom Checklist (SCL), the Medical Outcomes Study SF-36 Health Survey, the Center for Epidemiological Studies Depression Scale, the Impact of Events Scale, and the Sexual Functioning Questionnaire-Female. RESULTS: At a mean of 23.8 months after RRSO, overall quality of life was similar to that reported for the general population and for breast cancer survivors. Estrogen deprivation symptoms, particularly vaginal dryness (35.2%) and dyspareunia (27.7%), were commonly bothersome. Genital symptoms resulting in sexual dysfunction were the most significant predictors of satisfaction with surgery. The prevalence of depression (20.4%) was similar to that of the general population, but a significant proportion of the group (20.7%) continued to report significant ovarian cancer-specific worries despite surgery. CONCLUSION: Vaginal symptoms are bothersome to women who have undergone RRSO, but overall health and psychological outcomes are not impaired. Although coital symptoms may not be a direct consequence of RRSO, they are the most important predictors of satisfaction. A proportion of women continue to report worries about ovarian cancer after surgery, and these women are at risk for psychological distress.

Gastrointestinal adenocarcinoma arising in a mature cystic teratoma of the ovary.

BACKGROUND: Mature cystic teratoma of the ovary (MCTO) is the most common ovarian germ cell neoplasm and is usually diagnosed in early adulthood. Malignant transformation is rare, occurring in approximately 2% of all cases. Though malignant transformation can occur from any of the embryonic germ layers, the most common malignancy arising in these otherwise benign tumors is squamous cell carcinoma. CASE: We present a patient with a MCTO where malignant transformation of gastrointestinal epithelium resulted in moderately differentiated adenocarcinoma. After 3 years of follow-up, she remains free of disease. CONCLUSION: Although gastrointestinal epithelium is often found in MCTOs, adenocarcinoma arising from this cell type is uncommon. This is the third reported case of adenocarcinoma arising in gastrointestinal epithelium of a MCTO.

Primary vaginal melanoma: a critical analysis of therapy.

BACKGROUND: Primary vaginal melanoma is a rare and highly malignant disease. The impact of therapy on outcomes is poorly understood. METHODS: Records of all patients treated for primary vaginal melanoma at Memorial Sloan-Kettering Cancer Center from 1977 to 2001 were reviewed. Survival analysis was performed based on appropriate patient, tumor, and treatment variables. Pathologic materials were reviewed to confirm the original diagnosis and examine appropriate clinicopathologic features. RESULTS: Thirty-five women were treated for vaginal melanoma; the primary treatment selected was surgical for 69% (24) and radiotherapy for 31% (11) of the patients. Surgical removal of the tumor was achieved in 92% (22) of the 24 patients selected for surgical therapy. At operation, radical excision with en bloc removal of involved pelvic organs was performed in 50% (12) of the 24 patients, a wide excision was performed in 42% (10), and a total vaginectomy was performed in 8% (2). Elective pelvic lymph node dissection was performed in 74% (26) of the 35 cases. Lymph node metastasis was found in only 8% (2) of these 26 patients. The overall median survival was 20 months. Primary surgical therapy was associated with longer overall survival (25 vs. 13 months; P =.039). Recurrence-free survival was not associated with the extent of surgery. None of the examined clinicopathologic features were associated with survival differences. CONCLUSIONS: The prognosis is poor for patients with primary vaginal melanoma. Improved clinical outcomes were associated with surgical removal of gross disease whenever possible. Because of the low rate of lymph node metastasis, elective pelvic lymph node dissection is not obligatory. In cases of surgically unresectable disease, primary radiation therapy is indicated.

Transperitoneal laparoscopic pelvic and para-aortic lymph node dissection using the argon-beam coagulator and monopolar instruments: an 8-year study and description of technique.

OBJECTIVE: The objective was to describe the results, technique, and complications of transperitoneal laparoscopic (LSC) pelvic and aortic lymph node dissection (LND) using the argon-beam coagulator (ABC) and monopolar electrosurgical instruments in women with gynecologic malignancies. METHODS: A retrospective chart review of 114 patients who underwent LSC pelvic and/or aortic LND in addition to other LSC procedures between 1/1994 and 12/2001 was conducted. All intraoperative complications and complications that occurred within the first 30 postoperative days were included. Complications were graded according to an institutional surgical secondary events reference. During the same time period, 89 patients underwent LSC followed immediately by laparotomy that included LND, resulting in a total of 203 cases. These 203 total cases are used as a denominator to determine the etiology of cases converted from LSC to laparotomy. Monopolar electrosurgical instruments or the 10-mm ABC (Conmed) set at 70 W with argon flow of 3-4 L/m min were used for laparoscopic nodal dissection. RESULTS: Sixty-one of 114 (53%) patients underwent pelvic LND, 35 (31%) underwent both pelvic and aortic LND, and 18 (16%) underwent aortic LND only. Mean patient age and body mass index were 53.3 years (range, 16 to 87 years) and 25 (range, 16 to 40), respectively. In addition, the mean number of pelvic and aortic lymph nodes removed was 10.7 (range, 1 to 39) and 5.7 (range, 0 to 21), respectively. The mean estimated blood loss was 151 mL (range, 25 to 600 ml) and the mean hospital stay was 2.8 days (range, 0 to 35 days). Overall, complications occurred in eight (7%) cases. There were no fatal complications, and no patient required conversion to laparotomy due to uncontrollable bleeding from the laparoscopic nodal dissection. Only 17 of 203 (8%) patients required conversion to laparotomy secondary to adhesions and unsatisfactory exposure. CONCLUSION: Laparoscopic pelvic and aortic LND for gynecologic malignancies can be satisfactorily performed in the majority of patients, with only 8% of patients requiring conversion to laparotomy due to adhesions or unsatisfactory exposure. The overall complication rate was 7% and was limited to grade 3 or less.

A fertility-sparing alternative to radical hysterectomy: how many patients may be eligible?

OBJECTIVE: To determine the percentage of patients with early-stage cervical cancer who may be eligible for fertility preservation with laparoscopic radical vaginal trachelectomy (LRVT). METHODS: We retrospectively reviewed the records of patients who underwent a radical hysterectomy for invasive cervical cancer at our institution from 12/85 to 8/01, before our use of LRVT at Memorial Sloan-Kettering Cancer Center. Institutional eligibility criteria for LRVT were applied. Patients > or =40 years of age were considered ineligible. RESULTS: We identified 435 patients who had undergone radical hysterectomy for cervical cancer; 186 were age < 40 at surgery and constituted our study population. Eighty-nine (48%) patients may have been eligible by our pathologic criteria. In 12 patients, LRVT may have been aborted or altered because of unexpected disease spread. CONCLUSION: A significant number of patients < 40 with early-stage cervical cancer may be pathologically eligible for LRVT and should be counseled on this preoperatively.

Total laparoscopic radical hysterectomy with pelvic lymphadenectomy using the argon-beam coagulator: pilot data and comparison to laparotomy.

OBJECTIVES: The aim of this study was to describe the feasibility and outcome of total laparoscopic radical hysterectomy with pelvic lymphadenectomy for stage I cervical cancer using the argon-beam coagulator. METHODS: A retrospective review was performed of patients with FIGO stage IA1-IB1 cervical cancer who underwent a total laparoscopic approach for definitive surgical treatment. Comparison was made to a cohort of 195 patients who were treated with laparotomy. RESULTS: Between 12/2000 and 12/2002, 19 patients were offered the laparoscopic approach. The procedure was completed laparoscopically in 17 patients (89.5%). Two patients, in the beginning of the study, underwent conversion to laparotomy, 1 due to parametrial bleeding and 1 due to pelvic adhesions and cystotomy. Mean age was 42.6 years (range, 30-69 years); mean body mass index was 23.1 (range, 18-30); FIGO stage included IA1 with LVI (2), IA2 (6), IB1 (11). Mean pelvic lymph node count was 25.5 (range, 15-39), and 1 patient (5.3%) had positive nodes. Mean estimated blood loss was 301 cc (range, 75-1500 cc) compared to 693 cc in the laparotomy group (P < 0.01), mean operating time was 371 min (range, 230-600 min) compared to 295 min in the laparotomy group (P < 0.01), and mean hospital stay was 4.5 days (range, 3-11 days) compared to 9.7 days in the laparotomy group (P < 0.01). There were no ureteral injuries or fistula formation. All patients remain clinically disease free at the time of this report. CONCLUSIONS: Total laparoscopic radical hysterectomy with pelvic lymphadenectomy for selected patients with stage I cervical cancer is feasible, safe, and associated with a low morbidity in the pilot phase. Estimated blood loss and postoperative hospitalization appear shorter than historical controls, at the cost of longer operating time. Oncologic outcome requires longer follow-up.

Use of an ureteroileocecal appendicostomy urinary reservoir in patients with recurrent pelvic malignancies treated with radiation.

OBJECTIVE: Evaluation of a modified right colon urinary reservoir in a heavily radiated patient population undergoing pelvic exenteration. METHODS: A retrospective chart review was performed on all patients with recurrent gynecologic, colorectal, and urological tumors who underwent total pelvic or anterior exenteration and urinary diversion from 3/01 to 7/03 using an ureteroileocecal appendicostomy urinary reservoir. RESULTS: Fourteen patients were identified over the study interval. The mean age of the patients was 53 years (range, 22-78 years). All patients received external beam, intracavitary, or a combination of both radiation treatment modalities to the pelvis preoperatively. Eight patients received intraoperative radiation therapy (IORT) at a mean dose of 16.25 Gy (range, 12.5-17.5 Gy). The primary sites of disease were as follows: cervix, five; prostate, three; uterus, two; colon/rectum two; and one each for vulva and bladder. Complete stomal continence was achieved in all patients after a median follow-up of 10 months (range, 2-31 months). Two patients experienced a traumatic disruption of the stomal-skin anastomosis in the early postoperative period (postoperative days 7 and 14). One late complication related to the ureterointestinal anastomosis was observed and consisted of an anastomotic stricture managed conservatively. One patient experienced an entero-pouch fistula following re-exploration for an acute postoperative hemorrhage. CONCLUSION: The early outcomes using the ureteroileocecal appendicostomy urinary reservoir in heavily radiated patients demonstrate the technical feasibility of this design as both minimal early stoma and ureterointestinal complications may occur. Longer postoperative follow-up will be required to address the late outcomes of this procedure and its ultimate use in this population.

Improved optimal cytoreduction rates for stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancer: a change in surgical approach.

OBJECTIVE: To determine the impact of the incorporation of extensive upper abdominal debulking procedures on the rates of optimal primary cytoreduction and complications in stages IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal carcinomas. METHODS: Two groups of patients were identified for comparison. Group 1, the control group, consisted of 70 consecutive patients who underwent "standard" primary cytoreductive surgery before May 2000. Group 2, the study group, was composed of 70 consecutive patients who underwent surgery after January 2001, during which time, a more comprehensive debulking of upper abdominal disease was used, including diaphragm stripping/resection, splenectomy, distal pancreatectomy, liver resection, resection of porta hepatis tumor, and cholecystectomy. RESULTS: The median age of the entire cohort was 60 years (range, 36-88 years). The majority had stage IIIC disease (86%) and serous histology (76%). Optimal cytoreduction (residual disease