Early ovarian cancer: what is the staging impact of retroperitoneal node sampling?

BACKGROUND: Comprehensive surgical staging of apparent early-stage epithelial ovarian cancer includes peritoneal washings, biopsies, and retroperitoneal lymph node dissection. Unresolved is the relative frequency or importance of the lymph node dissection. OBJECTIVES: (1) To determine the site(s) of microscopic metastatic disease in women undergoing a comprehensive staging for apparent early-stage cancer of the ovary; (2) to identify those women with metastases in the retroperitoneal lymph nodes alone. METHODS: Between 1985 and 2000, we reviewed all records of women at cancer centres in Winnipeg, Ottawa, and Saskatoon who had undergone a "staging laparotomy" for an apparent early-stage IA epithelial cancer of the ovary. Histology, tumour grade, initial and final surgical stage, and the site(s) of metastatic disease were recorded for all cases. RESULTS: Forty-three of the 128 women (34%) had a final surgical stage of II or III. Sixteen women had positive pelvic biopsies, while 19 had microscopic upper abdominal disease. Eight women had positive retroperitoneal nodes, and in only 2 of these women, disease was found in the retroperitoneal nodes alone. In the 8 women with nodal disease, 5 had grade 3 tumours and 6 had serous histology tumours. CONCLUSION: Comprehensive staging is important to identify women with metastatic disease. Solitary nodal metastases are predominantly found in grade 3 and serous tumours.

The benefits of comprehensive surgical staging in the management of early-stage epithelial ovarian carcinoma.

OBJECTIVE: The management of understaged patients with apparent clinically early ovarian cancer is difficult. Options include offering chemotherapy based on histopathologic factors or reoperation to obtain the necessary information needed to assign an accurate surgical stage. This study aims to compare these two approaches and to define the role of staging surgery in this common patient population. METHODS: Retrospective chart reviews were carried out at the Universities of Manitoba and Saskatchewan over the period 1975 to 1999. Demographic data and surgical findings were abstracted and entered into a computerized database for analysis. Patients not having surgical staging procedures were offered platinum-based chemotherapy based on high tumor grades, dense adhesions, and presence of surface excrescences or large necrotic areas. Patients with surgically proven stage I disease were treated with no further therapy regardless of histopathologic factors. Descriptive statistics are used to summarize the data. Logistic and Cox regression models are used to identify significant predicting factors for recurrences and progression-free intervals. RESULTS: One hundred and thirty-eight patients presented with tumor macroscopically confined to the ovary at the time of laparotomy. The median age at presentation is 56.5 (18-90). The histology distribution was serous tumor in 28.3%, mucinous in 26.1%, endometrioid in 23.2%, clear cell in 14.5%, anaplastic in 2.2%, and mixed types in 5.8%. The grade distribution was 47.1% grade 1, 27.5% Grade 2, and 25.4% Grade 3. Sixty-eight percent of the patients had a comprehensive surgical staging procedure initially. Thirty-six percent of these patients were found to have extraovarian metastases and were subsequently treated with adjuvant chemotherapy. Forty-three percent of those not having staging laparotomy were offered chemotherapy based on high risk factors only. At a median follow-up of 58 months. 77% of patients remained disease-free and 23% had recurrent disease. Of 60 patients with surgically proven stage I treated expectantly, 6 (10%) recurred, whereas of 25 unstaged patients treated expectantly due to lack of risk factors 7 (28%) recurred (P = 0.036). In patients treated expectantly, a significant survival advantage was noted in the staged group. Logistic regression showed age (OR 1.032, P = 0.043), high grade (OR 4.16, P = 0.003), and lack of a proper staging surgery (OR 2.62, P = 0.032) to be important factors predicting recurrence. In terms of progression-free interval, only age (OR 1.027, P = 0.048) and tumor grade (OR 3.62, P = 0.05) are significant predictors. CONCLUSION: Absence of surgical pathologic high-risk factors is inferior to comprehensive staging laparotomy findings in guiding recommendations for subsequent adjuvant therapy. Patients who have not been properly staged stand a significant risk of recurrent disease despite more frequent use of chemotherapy. All clinically early-stage ovarian cancer patients should be considered for comprehensive staging surgery prior to further treatment recommendations.

Antiestrogens affect both pathways of killer cell-mediated oncolysis.

BACKGROUND: Our previous studies indicate that antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune oncolysis induced by various killer cells. The underlying mechanism(s), however, have not been fully elucidated. MATERIALS AND METHODS: Ovarian carcinoma cells freshly isolated from cancer patients and the human erythroleukemia cell line, K562 were used as targets for killer cells and/or the anti-Fas monoclonal antibody, CH-11 in 51Cr release assays. In a number of experiments, extracellular Ca++ was chelated by EGTA/MgCl2 to distinguish Ca(++)-dependent perforin/granzyme pathway from Fas/FasL pathway. Fas expression was studied by flow cytometry. RESULTS: Ovarian carcinoma cells were sensitized by antiestrogens towards enhanced cytolysis mediated by autologous cytotoxic lymphocytes. Antiestrogens also significantly augmented the killing of ovarian carcinoma cells triggered by anti-Fas monoclonal antibody. Flow cytometry analyses showed an upregulation of Fas (CD 95/Apo-1) upon TX or TO treatment in a number of cases. By contrast, antiestrogen treatment did not induce Fas expression in the Fas-negative K562 cells; yet, natural killer cell-mediated cytotoxicity against K562 was augmented by antiestrogens and maximal lysis was achieved when both target and effector cells were treated. The presence of Ca++ chelator (EGTA/MgCl2) in the assay abrogated killing of K562 and its antiestrogen--mediated augmentation. This indicates the involvement of the perforin/granzyme pathway. CONCLUSION: Antiestrogens can influence both Fas/FasL and perforin/granzyme pathways of killer cell--mediated oncolysis.

Antiestrogens sensitize human ovarian and lung carcinomas for lysis by autologous killer cells.

BACKGROUND: The antiestrogens tamoxifen (TX) and toremifene (TO) were shown previously to enhance the lysis of target cells by natural killer cells (NK), lymphokine activated killer (LAK) cells, and by cytotoxic T lymphocytes (CTL). MATERIALS AND METHODS: CTL were cultured from lung cancer tissue and from ascites fluid of ovarian carcinoma patients with the aid of human recombinant interleukin-2 (hrIL-2). The target, effector or both cell populations were pretreated by TX, TO and/or with human recombinant interferon-alpha (IFN-alpha). RESULTS: Significant enhancement of cytotoxicity occurred when the tumor targets or both the target and effector cells were treated with TX, TO or when these drugs were used in combination with IFN-alpha. The lytic activity of CTL cultured from draining lymph nodes of lung cancer patients, was also observed after similar treatment. The lytic effect of autologous LAK cells derived from peripheral blood was increased to a lesser extent, which could be amplified by additional treatment with IFN-alpha. CONCLUSIONS: The antiestrogens TX and TO and IFN-alpha enhance the lysis of autologous tumor cells by CTL and LAK effectors.

Clinically apparent early stage invasive epithelial ovarian carcinoma: should all be treated similarly?

OBJECTIVES: The role of adjuvant therapy in patients with early stage ovarian carcinoma has not been clearly defined. Most randomized trials examining this issue have not used the vigorous staging exploration accepted as today's standard. This report examines the natural history of patients after surgically documented stage 1 ovarian carcinoma followed expectantly. METHODS: A retrospective chart review was carried out using strict criteria to include only patients who had an adequate staging procedure performed by gynecologic oncologists following a fixed protocol from 1987 to 1997. Patients' demographic data as well as current disease status were abstracted and analyzed. RESULTS: A total of 80 comprehensive surgical staging procedures were carried out over a 10-year period for apparent stage 1 ovarian cancer at the time of exploratory laparotomy. Fifty cases were true surgicopathological stage 1. It was found that serous and anaplastic tumors were more likely than other subtypes to be upstaged by the procedure. Further follow-up confirmed the excellent prognosis of early stage serous, endometrioid, and mucinous tumor with only one recurrence noted in an extraabdominal location in a patient with serous histology with no postoperative adjuvant therapy. Clear cell histology stands out as a significant recurrence risk (33%) despite an initially negative surgical assessment. CONCLUSION: Careful surgical exploration can identify a group of patients with early stage epithelial ovarian carcinoma who will benefit little from further adjuvant therapy. Patients with clear cell histology prove to be at a high risk for recurrence even at an early stage such that chemotherapy should be considered.

Does debulking surgery improve survival in biologically aggressive ovarian carcinoma?

Aggressive tumor reduction surgery has been widely used in patients with advanced stage epithelial ovarian carcinoma before initiation of cytotoxic chemotherapy. No randomized controlled trial has been carried out to confirm the benefits of such procedures. To examine the role of cytoreductive surgery in the management of stage 2 and 3 patients with epithelial ovarian carcinoma treated with postoperative adjuvant platinum-based chemotherapy, survival analysis was carried out on patients with initial microscopic disease documented on staging laparotomies, patients with large volume of disease at time of exploration and tumor reduced to microscopic residuals, and patients who were suboptimally debulked with more than 2-cm residual disease. Twenty-four, 81, and 191 patients were identified from a computerized data base, respectively. Kaplan-Meier survival estimates showed that 62% with initial microscopic residual are alive with no evidence of disease at 5 years and 56% of patients left with microscopic residuals after tumor reduction are alive and well at 5 years. There was no statistical significant difference between these two groups. The groups are equivalent with respect to known adverse prognostic factors. In contrast, 5-year survival in the suboptimal debulked group was significantly lower at 15%. Debulking surgery to achieve microscopic residual disease improved the prognosis in patients with initial large volume of disease. Survival was similar to survival in patients with microscopic disease at time of exploration. The beneficial effect may be attributed to the removal of chemoresistant clones in bulky tumors. Tumor reduction surgery remains important in the management of advanced stage epithelial ovarian carcinoma.

Malignant mixed mesodermal ovarian tumor treatment and prognosis: a 20-year experience.

Mixed mesodermal sarcoma of the ovary is a rare clinical entity. To review the epidemiology, prognostic factors, and treatment results related to primary ovarian sarcoma at our center, a retrospective chart review of all patients referred for ovarian cancer was carried out from 1974 to 1994. Cases with confirmed pathologic diagnosis of primary mixed mesodermal ovarian sarcomas were selected, forming the present study group. Thirty-six charts were identified. The median age at presentation was 67.5 years. Findings at laparotomy demonstrated extraovarian metastasis in 33/35 patients. Total abdominal hysterectomy and bilateral salpingo-oophorectomy +/- omentectomy were performed in 34 patients, with 22 patients left with macroscopic residual disease after surgery. Follow-up adjuvant chemotherapy consisting of cisplatin and doxorubicin was administered to 29/36 patients. Follow-ups ranged from 1 to 11 years with a median of 2 years. As with epithelial ovarian cancer, residual disease after initial surgery is an important prognostic factor. Thirteen patients had a second-look laparotomy. Five patients were positive for disease. Eight patients, one of whom recurred, were histologically negative. The patients with positive second-look findings, as well as all those who recurred clinically, subsequently died within 12 months despite trials with different second-line chemotherapeutic agents. Survival analysis showed a median survival of 3 years among patients treated with combination cytotoxic chemotherapy. Primary ovarian sarcomas make up about 2-3% of all ovarian cancer cases seen in our center. These are often very aggressive tumors with widespread metastasis at the time of presentation, making optimal tumor debulking difficult. The combination of cisplatin and doxorubicin appears to have activity resulting in a survival of 35% at 5 years. Second-look surgery offers little helpful information on the management of these tumors.

Early ovarian cancer: value of a negative staging laparotomy.

OBJECTIVE: To assess the risk of recurrence in patients with stage I (negative cytology) epithelial ovarian cancer receiving no adjuvant therapy. METHODS: Between 1976 and 1991, 51 patients with apparent stage I ovarian cancer underwent a comprehensive surgical staging that included: peritoneal cytology, omentectomy, pelvic and para-aortic lumphadenectomy, peritoneal biopsies and either unilateral salpingo-oophorectomy or TAH and BSO. RESULTS: Eleven of 51 patients (22%) were found to have stage II or III disease based on a positive staging laparotomy. Thirty-seven of 40 patients with stage I disease received no further therapy. There was one recurrence (stage 1C - grade 1) in patients with surgical stage 1C while there were no recurrences in patients with either stage 1A or 1B disease. CONCLUSION: This study concludes that surgical staging in apparent early stage ovarian cancer can identify a group of patients that require surgical therapy alone.

Peritoneovenous shunt for palliation of gynecologic malignant ascites.

BACKGROUND: Ascites is a common sequela of advanced or recurrent gynecologic malignancies, such as carcinoma of the ovary, fallopian tube, or endometrium. Symptomatic treatment with repeated paracentesis is the initial management after failure of chemotherapy. STUDY DESIGN: This study was done to evaluate the safety and effectiveness of a peritoneovenous shunt (PVS) in the palliation of these patients with recurrent ascites. A retrospective review of 25 patients having a PVS between 1982 and 1992 was performed. RESULTS: The 25 patients consisted of 21 patients with carcinoma of the ovary, two with primary carcinoma of the peritoneum, one with carcinoma of the endometrium, and one patient with carcinoma of the fallopian tube. The mean weight and abdominal girth decreased after shunt insertion (p < 0.001). Gastrointestinal dysfunction and dyspnea also improved with PVS insertion. There was no change in mean Karnofsky score after placement of a PVS. Two patients died within ten days postoperatively. The median survival period was 80 days and shunt occlusion occurred in four patients. CONCLUSIONS: The insertion of a PVS is effective in relieving refractory malignant ascites in gynecologic malignancies. The impact on quality of life requires further study.

Should selective paraaortic lymphadenectomy be part of surgical staging for endometrial cancer?

Surgical staging of adenocarcinoma of the endometrium attempts to identify the true distribution of disease. The survival value of paraaortic lymphadenectomy selectively performed in patients with histologic risk factors is unproven. The objective of this study was to determine if a staging procedure that did not include paraaortic lymphadenectomy predicted recurrence-free survival in disease surgically confined to the uterus. Between 1978 and 1990, 273 patients underwent surgical staging. Two hundred and sixty-nine were clinical stage I and 4 were stage II. The staging procedure included peritoneal cytology, TAH and BSO, and pelvic lymphadenectomy. Postoperative therapy, if any, consisted of whole pelvis and vault radiotherapy in disease confined to the uterus and systemic chemotherapy in patients with extrauterine disease. Surgical staging resulted in 220 (81%) stage I, 20 (7%) stage II, 27 (10%) stage III, and 6 (2%) stage IV. Eighty-eight patients in stages I and II had deep myometrial invasion or a grade 3 tumor. There were 12 recurrences, 8 in stage I and 4 in stage II, in patients with disease confined to the uterus. Four patients (1.7%) recurred outside the pelvis. Had paraaortic lymphadenectomy been performed in patients with risk factors, this would have mandated 88 dissections to potentially benefit 4 patients. We conclude that paraaortic lymphadenectomy would have been of small benefit to these surgically staged patients.

Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Given the potential for improved tolerance, a trial was initiated to compare the toxicity and efficacy of a standard regimen of cisplatin-cyclophosphamide (75 mg/m2 and 600 mg/m2, respectively) with an experimental regimen of carboplatin-cyclophosphamide (300 mg/m2 and 600 mg/m2, respectively) in women with postoperative macroscopic residual ovarian cancer. PATIENTS AND METHODS: Between 1985 and 1989, 447 (417 eligible) patients were randomized. Treatment arms were well balanced; most patients had stage III (82%), grade 3 (54%) tumors with bulky residual (greater than 2 cm in 59%), and good performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1, 77%). Response was assessed after six 4-week cycles. RESULTS: The treatments were equally deliverable, with 76% of patients completing their allocated regimen. The reported reasons for failure to complete treatment differed; toxicity/refusal predominated on the cisplatin arm, and progressive disease predominated on the carboplatin arm (P = .0092). Cisplatin-treated patients were more likely to develop neuropathy and nephropathy, and carboplatin patients experienced myelosuppression, particularly thrombocytopenia. Efficacy was similar, with no significant differences for the cisplatin and carboplatin arms in clinical response rate (57% v 59% in those with measurable disease), pathologic response rate (52% v 54% in those suitable for relaparotomy), time to progression (median, 56 v 58 weeks), or overall survival (median, 100 weeks v 110 weeks). Time to progression and survival were predicted by residual disease size, performance status, and treatment center (with those treated at centers that accrued more patients doing better). CONCLUSION: Neither regimen is optimal in that relapse remains the norm. It may be inappropriate to expect that any single regimen can be an effective therapy for all patients with advanced ovarian cancer. Both cisplatin and carboplatin are likely to have a role in future treatment strategies.

Glassy cell carcinoma of the cervix: a bimodal treatment strategy.

Glassy cell carcinoma of the cervix is a distinct clinicopathologic entity. This infrequent pathologic subtype is an aggressive biologic tumor associated with a rapid clinical course and poor outcome with conventional treatment modalities in the majority of cases. In a 12-year period from July 1976 to June 1988, 32 cases of glassy cell carcinoma of the cervix were identified. This accounted for 5.3% of all cervical carcinomas. The mean age was 10 years younger than that of other histologic subtypes. A disproportional number of patients with glassy cell carcinoma had malignancies of early clinical stages. The 5-year survival of patients with Stage IB glassy cell carcinoma of the cervix was 45% when treated with primary radical surgery in contrast to 90% for squamous cell and 78% for adenocarcinoma. When bimodal therapy with radical surgery and radical radiotherapy was used, the survival of patients with Stage IB glassy cell carcinoma improved to 87%. Survival of patients with Stage II glassy cell carcinoma of the cervix improved from 50% to 85% with combined radical surgery and radiotherapy. Despite a combination of radical surgery and radiotherapy, complications were minimal.

Treatment of recurrent and metastatic adenocarcinoma of the endometrium with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate.

We conducted a retrospective review of 44 patients with metastatic or recurrent endometrial carcinoma treated with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate. Thirty-six women had metastatic disease; eight had recurrent disease. In the metastatic group, 12 women had positive peritoneal cytology as the only criterion for metastatic disease. Grade 1 tumors represented 25%, grade 2, 47.7%, and grade 3, 27.3%. The series was divided into four groups based on disease volume before chemotherapy: positive peritoneal cytology only (N = 12), microscopic (N = 11), macroscopic less than 2 cm (N = 6), and macroscopic greater than 2 cm (N = 15). Fifteen patients had measurable disease and eight (53%) had an objective response. The median survival was 31 months for the whole group. Median survivals were not reached for the positive peritoneal cytology only and the microscopic groups. Median survival for the macroscopic less than 2 cm and greater than 2 cm groups were 15 and 10 months, respectively (P less than .0001). The volume of disease was the most important factor in determining survival as well as the time to progression (P less than .0001). The distribution of grade was similar in all groups (P = .88), and grade did not predict survival (P = .80) or recurrence (P = .87). The significant number of low-grade lesions in our series as well as the importance of positive cytology as a predictor of survival underscore the need for surgical pathologic staging in an effort to identify those patients in need of adjuvant therapy.

Surgery without adjuvant chemotherapy for early epithelial ovarian carcinoma after comprehensive surgical staging.

From January 1981 to December 1987, 82 patients with carcinoma of the ovary, Stages 1A, 1B, and 1C (cytology negative) (FIGO 1988), were enrolled in this study following accurate surgical staging. No patient received adjunctive therapy and all were followed from 2 to 6 years with a mean duration of follow-up of 4 years. Sixty-eight patients were eligible for review--thirty-nine Stage 1A, six Stage 1B, and twenty-three Stage 1C (twenty-one with tumor rupture, two with excrescences). The mean age was 48.8 years. Three patients had a recurrence of their disease (one death). Forty patients in this series were Stage 1A or 1B (well or moderately well differentiated, no excrescences, no rupture). Only 1 patient in this group (with clear cell carcinoma) has recurred, suggesting that this patient population can be followed without adjunctive therapy. Adhesions or rupture in this series did not affect outcome. Clear cell tumors may have an ominous prognosis despite apparent local disease.

Tubular Krukenberg tumor in pregnancy with virilization.

A case of tubular Krukenberg tumor in pregnancy with virilization is presented. The pathology is reviewed. This rare tumor must be distinguished from a Sertoli-Leydig tumor. The index case adds to the previously recorded eight cases. All nine cases reviewed presented with progressive virilization between the third and eighth month of gestation, which regressed after surgery. The fetal outcomes of seven cases have been recorded. The fetuses were all female and of these five were virilized. A gastric primary was found in five cases. A primary breast carcinoma was postulated in another. In the remaining cases either no autopsy was performed or no primary tumor was found.

Carcinoma of female urethra. Manitoba experience: 1958-1987.

Fourteen female patients with primary urethral carcinoma were treated at the Manitoba Cancer Foundation in the last twenty-nine years. The relationship of natural history to the stage, location, and therapeutic modality has been reviewed. A higher stage and length of urethral involvement affected prognosis negatively, whereas lower stage had a positive prognostic effect and location of tumor had no prognostic influence. Two patients with Stage C, who failed to received inguinal node radiotherapy, died of disease recurring in the inguinal area. Patients who received inguinal radiation (3 patients Stages B, C, and D1) had no regional recurrence. It is suggested that, for all female urethral carcinoma, bilateral ilioinguinal nodes be included in the radiation field. For radical treatment, iridium 192 insertion in combination with external beam treatment is recommended.

Factor analysis of false-negative second-look laparotomy.

From January 1976 through December 1987, 155 patients with ovarian epithelial malignancy underwent a second-look laparotomy. Seventy-seven (50%) had a negative second-look. Recurrence after negative second-look occurred in 15 patients (19.5%). Of the factors analyzed, serous histology and residual disease after initial laparotomy were found to be of significance. Grade of tumor, stage, and ascites were not found to be of significance.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma.

A retrospective review of 280 patients with endometrial carcinoma who had peritoneal cytologic examination done at the time of laparotomy was undertaken. A positive cytologic finding was the only manifestation of extrauterine disease in 16 patients (6%). Four (25%) of these patients had a recurrence. Only 13 (5%) of 237 patients with negative cytologic findings had a recurrence. Positive peritoneal cytology is a marker for potential recurrence.

Adriamycin and cisplatin in the treatment of stage III and IV epithelial ovarian carcinoma.

A total of 342 eligible, previously untreated patients with Stage III or IV epithelial ovarian carcinoma were treated with Adriamycin and cisplatin, both at 50 mg/m2, for nine courses. Of the 210 patients who had clinically detectable disease after initial surgery, 85 (41%) had a complete clinical response and 45 (21%) had a partial clinical response. A total of 197 were clinically free of disease at the completion of chemotherapy and 175 of these had a second-look laparotomy; 55 had no macroscopic or microscopic evidence of residual disease after multiple random biopsies were examined histologically (complete surgical/histologic response). The major determinants of complete surgical/histologic response were diameter of largest residual tumor prior to treatment, ECOG performance status, and grade, patients with grade 3 tumors having a higher complete response rate than those with grade 1 or 2 tumors. The major determinants of survival were ECOG performance status and diameter of largest residual tumor prior to treatment. Median survival of the total group was 1.8 years.