Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel vs. cisplatin and paclitaxel (GOG 158) and an update on GOG0 182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

Optimal therapy of advanced ovarian cancer: carboplatin and paclitaxel versus cisplatin and paclitaxel (GOG158) and an update on GOG0182-ICON5.

Mature results from GOG158 have clearly established carboplatin and paclitaxel as an effective and well-tolerated standard regimen, providing a basis for the reference arm in GOG0182-ICON5, an ongoing multiarmed phase III trial of the Gynecologic Cancer InterGroup (GCIG) evaluating the incorporation of newer cytotoxic agents. Results from GOG158 will be reviewed, including an analysis of second-look surgical outcomes, followed by an update on the current status of GOG0182-ICON5.

Evaluation of chemoresistance markers in women with epithelial ovarian carcinoma.

OBJECTIVE: Preliminary studies have suggested that lung resistance protein (LRP), multidrug resistance protein (MRP), and p27 may be useful markers of chemoresistance. Our goal was to evaluate the expression of LRP, MRP, and p27 in normal ovaries and chemosensitive and chemoresistant ovarian carcinomas. METHODS: Fourteen women with normal ovaries and fifty women with epithelial ovarian carcinoma who underwent cytoreductive surgery from 1996 through 1998 had specimens stained with immunocytochemistry for LRP, MRP, and p27. All women received paclitaxel/platinum-based chemotherapy. Twenty-nine women had a disease-free survival (DFS) of at least 12 months after completion of chemotherapy (sensitive) and 21 women had persistent disease during treatment (resistant). RESULTS: Evaluation of LRP expression revealed significant differences between the normal ovaries and cancers in both the epithelial (57% vs 90%, P = 0.03) and stromal (86% vs 32%, P = 0.001) components. Evaluation of MRP expression revealed significant differences between normal ovaries and cancers in the epithelial component (7% vs 66%, P = 0.001) but not in the stromal component (14% vs 4%, P = 0.1). Evaluation of p27 revealed significant reductions in expression in cancers compared with normal ovaries for both the epithelial (90% vs 55%, P = 0.02) and stromal (88% vs 5%, P = 0.001) components. Comparison between the chemosensitive and chemoresistant groups revealed no significant differences in expression of LRP and MRP, in either the epithelial or stromal component, but significantly lower levels of p27 were expressed in the epithelial component of the chemoresistant group (P = 0.01). CONCLUSIONS: The expression of LRP, MRP, and p27 is significantly different in ovarian cancers compared with normal ovaries. Low levels of p27 expression are associated with chemoresistance; however, LRP and MRP expression are not prognostic for chemosensitivity.

Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis.

OBJECTIVE: BRCA-1 and BRCA-2 germline mutations increase the risk of ovarian and breast cancer. Primary cancer of the fallopian tube is rare; however, recent evidence suggests that patients harboring a germline mutation conferring an increased risk of ovarian cancer may be at risk for fallopian tube cancer as well. We discuss the finding of occult fallopian tube cancer diagnosed at surgical prophylaxis in women harboring BRCA-1 mutations. METHODS/RESULTS: Two patients undergoing surgical prophylaxis to address an increase in ovarian cancer risk were discovered to harbor occult primary fallopian tube carcinoma on final pathology review. Mutational analysis confirmed the presence of a deleterious mutation in BRCA-1 in both patients. CONCLUSION: Currently, consensus opinions regarding ovarian cancer surgical prophylaxis in gene mutation carriers do not include hysterectomy as part of the preventative procedure. This report as well as a growing number of cases of fallopian tube cancer reported in known BRCA-1 and BRCA-2 mutation carriers has important implications for recommendations regarding surgical prophylaxis in these women.

Alterations in SPARC and VEGF immunoreactivity in epithelial ovarian cancer.

OBJECTIVE: Secreted protein, acidic and rich in cysteine (SPARC), is a matricellular protein that modulates cell adhesion and growth. It is thought to play a decisive role in tissue remodeling and angiogenesis. Alterations in SPARC expression have been observed in a variety of solid tumors; however, no consistent pattern of deregulation has been characterized. Vascular endothelial growth factor (VEGF) has emerged as an important regulator of tumor neovascularization. Recent work has shown that SPARC modulates the mitogenic activity of VEGF in normal endothelium. While its role in malignant transformation remains elusive, SPARC may contribute to tumor propagation and invasion. This study examines the immunoreactivity of SPARC and VEGF associated with neoplastic transformation of the ovary. METHODS: Immunostaining for VEGF and SPARC protein was performed on 62 archival specimens. RESULTS: Fourteen normal ovaries and 48 ovarian carcinomas were evaluated. SPARC was detected in the stroma of 63% of ovarian carcinomas. In contrast, SPARC was observed in the stroma of only 29% of normal ovaries (P = 0.02). Furthermore, SPARC was limited in normal ovaries to premenopausal patients, juxtaposed either with vesiculated follicles or within the corpus luteum. VEGF was observed in 42% of ovarian carcinomas with immunoreactivity confined to tumor cells. The level of VEGF immunoreactivity was significantly higher in ovarian carcinoma compared to normal ovary epithelium (42 vs 7%, P = 0.02). CONCLUSIONS: Immunoreactivity of SPARC and VEGF is heightened in association with ovarian carcinoma, with a distinct distribution of SPARC in the stroma of neoplastic ovaries and VEGF within tumor cells. No obvious pattern of coincident SPARC and VEGF immunoreactivity was detected. These results indicate the possibility of an aberration in the interaction that has been described in normal endothelium between SPARC and VEGF in association with malignant transformation.

Phase I study of paclitaxel, carboplatin, and increasing days of prolonged oral etoposide in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study.

PURPOSE: Given the activity of prolonged oral etoposide in platinum and paclitaxel-resistant ovarian carcinoma, a phase I trial was conducted that combined increasing days of oral etoposide therapy with paclitaxel and carboplatin in chemotherapy-naive patients with ovarian peritoneal and tubal carcinoma to establish a maximum-tolerated dose (MTD) of this combination. PATIENTS AND METHODS: Paclitaxel at 175 mg/m(2) given over 3 hours and carboplatin at an area under the curve of 5 were administered on day 1 followed by oral etoposide 50 mg/m(2)/d beginning on day 2. The number of days of etoposide therapy was escalated on the basis of toxicity. Toxicity end points included neutropenic sepsis, grade 4 thrombocytopenia, or grade 3 neutropenia or thrombocytopenia during etoposide administration. Cycles were repeated every 21 days for a maximum of six courses. Due to hematologic toxicity, the duration of the paclitaxel infusion was decreased to 1 hour for a second stage of accrual. RESULTS: Of 52 patients studied, 29 were in the first stage of accrual. Dose-limiting toxicity occurred with 8 days of oral etoposide, making the MTD six days of therapy. Twenty-three patients were entered into the second stage of accrual. Dose-limiting toxicity occurred at 12 days of oral etoposide, making the MTD 10 days of therapy. Three patients developed acute myeloid leukemia 16, 27, and 35 months after receiving a cumulative dose of 200 mg/m(2), 1,200 mg/m(2), and 2,400 mg/m(2), respectively. CONCLUSION: One-hour paclitaxel, carboplatin, and oral etoposide at 50 mg/m(2)/d for 10 days is tolerable without supportive therapy. The leukemogenic potential is cause for concern and precludes its use in chemotherapy-naive ovarian carcinoma.

The prognostic significance of radiation dose and residual tumor in the treatment of barrel-shaped endophytic cervical carcinoma.

OBJECTIVE: The aim of this study was to evaluate the impact of total radiation dose on residual tumor and the prognostic significance of persistent disease in women with bulky, barrel-shaped cervical carcinoma who received definitive radiation followed by adjuvant hysterectomy. METHODS: The medical records of 57 patients with bulky endophytic cervical carcinoma treated at the University of Washington between 1976 and 1997 were reviewed. All patients received external beam pelvic radiotherapy supplemented by intracavitary brachytherapy, followed by extrafascial hysterectomy 6 to 8 weeks later. RESULTS: The mean pretreatment tumor diameter was 5.9 cm, with a range of 4-9 cm. Total radiation dose to point A ranged from 5040 to 9700 cGy, and the mean for the group was 7966 cGy. Residual disease was present in 35 (61%) of the hysterectomy specimens. The frequency of cervical tumor sterilization correlated significantly with the mean radiation dose to point A (P = 0.016). Patients without histologic residual disease had a significantly improved outcome, with 95% of patients remaining clinically free of disease at last follow-up, versus 31% of those with residual disease (P < 0.001). As expected, the pelvic control rate was excellent (100%) in patients with complete tumor eradication compared to the group with residual tumor (44%). Those with no residual disease enjoyed a significantly improved survival compared to those with residual tumor (P < 0.001). Furthermore, a statistically significant higher survival was realized in patients harboring only microscopic residual compared to those with either macroscopically evident tumor residuum and/or positive surgical margins (P = 0.036). CONCLUSIONS: Higher radiation doses are associated with an improved likelihood of tumor eradication in the treatment of bulky, endophytic cervical cancer and complete tumor sterilization at adjuvant hysterectomy is predictive of significantly enhanced survival and pelvic control. The high rate of histologic tumor persistence in our series emphasizes the need for more efficacious therapies in patients with bulky endophytic cervical cancer and argues for escalation of radiation dose even when adjuvant hysterectomy is planned.

Pretreatment scalene node biopsy in gynecologic malignancy: prudent or passé?

OBJECTIVES: Surgicopathologic evaluation of the scalene fat pad is considered a critical step in the pretreatment evaluation of patients at our institution with cervical or corpus carcinoma when the periaortic lymph nodes (PAN) are involved. However, enthusiasm for this procedure at other centers has waned, largely due to a wide discrepancy in the reported rates of occult scalene node involvement. In an attempt to clarify the benefit of pretreatment scalene node sampling in gynecologic malignancies, we present our experience over the past 18 years. MATERIALS AND METHODS: We identified 57 patients who underwent scalene node sampling between 1980 and 1998. In 39 of 49 (80%), the decision to proceed with scalene node sampling was based entirely on histologically documented PAN metastases. In the remainder, scalene node sampling was prompted by the presence of suspicious clinical findings. RESULTS: Of the 49 patients included in the study, 33 had carcinoma of the cervix, while 16 had corpus carcinoma. Ninety percent of scalene node sampling was performed at the time of primary diagnosis. Overall, 9 patients (18%) had scalene node metastases. Notably, not a single patient with corpus cancer was found to have scalene node metastases in the absence of clinically evident scalene node enlargement independent of PAN status. In cervix cancer cases, the presence of grossly involved PAN was predictive of a high likelihood of scalene node metastases (44%), while no patient with occult PAN metastases had involvement of the scalene node. Only 1 minor complication was encountered following scalene node sampling. The 40 scalene node-negative patients were treated with either extended field radiation or whole abdominal radiation therapy, and 20% developed a major, RTOG grade >/=3 complication such as fistula formation, bowel obstruction, or ureteral stenosis. Only 1 case of mild radiation enteritis and cellulitis occurred during palliative radiation in the group of patients with scalene node metastases. CONCLUSIONS: Scalene node sampling may be of benefit in the pretreatment evaluation of patients with cervical carcinoma when PAN are grossly involved. Given that scalene node involvement satisfies the criteria for distant metastases, identification of such allows the clinician to avoid the morbidity of extended field radiotherapy in a setting without the chance for cure.

Impact of surgical staging in women with locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to evaluate the impact of surgical staging in the treatment and outcome of women with locally advanced cervical cancer. METHODS: Ninety-eight women with locally advanced cervical cancer treated between 1993 and 1997 were retrospectively reviewed. Survival probabilities were calculated by the Kaplan-Meier product limit method and compared with the log-rank test. RESULTS: Of the 98 women treated over the 5-year period, 86 were surgically staged: 61 by a retroperitoneal approach, 18 by laparoscopy, and 7 by laparotomy. Median blood loss was 120 cc and median length of hospitalization was 3 days. Preoperative CT scans (n = 55), when compared with surgical findings, missed macroscopic nodal disease in 20% and microscopic disease in 15% and overcalled disease in 10% of cases. Lymph node metastases were found in 45/86 patients (52%): 12 microscopic and 33 macroscopic. The highest level of nodes found to be involved was pelvic in 23, common iliac nodes in 3, para-aortic nodes in 14, and scalene nodes in 5 cases. Of the 86 patients, 49 received pelvic radiation, 27 received extended field radiation, and 10 were identified for palliative treatment only (5 scalene node metastasis, 5 extensive intraperitoneal disease). For node-negative patients, 5-year survival was 74%; for microscopic nodal involvement it was 58%; and for macroscopic involvement it was 39% (P = 0.007). Five-year survival for women with para-aortic node involvement was 52%. Number of nodes involved was a significant prognostic variable (P = 0.008). Patients who received chemotherapy had a 5-year survival of 68% compared to 35% for those who did not (P = 0.06). Factors which did not affect survival included age, histology, type of surgery, stage, and type of radiation (pelvic vs extended). CONCLUSION: Surgical staging of women with locally advanced cervical cancer can be performed with acceptable morbidity and it provided more accurate information than CT scans and resulted in a modification of the standard pelvic radiation field for 43% of our patients. The information obtained from surgical staging allows better individualization of therapy, which may improve overall clinical outcome.

A new technique for performing Syed template interstitial implants for anterior vaginal tumors using an open retropubic approach.

The Syed template (Alpha-Omega Services, Bellflower, CA) has been established as an advance in interstitial gynecologic brachytherapy. Unfortunately, enthusiasm for the technique is often tempered by certain tumor geometries which require blind insertion of the interstitial needles, potentially risking inaccurate placement of the radioactive sources and viscus perforation. These concerns arise particularly in the management of anterior vaginal tumors where difficulties in negotiating the pubic arch can prevent optimal needle placement. In answer to this problem, a technique utilizing an open retropubic approach for Syed template interstitial implants in anterior vaginal tumors under direct visualization is described. To date, six procedures have been performed. The disease entities include advanced cervical squamous cell carcinoma, clear cell carcinoma of the vagina, recurrent vaginal carcinoma, recurrent endometrial carcinoma, and urethral adenocarcinoma. Complete response was noted in five of six patients but persistent local control of disease was achieved in only one of five complete responses over a relatively short follow-up interval. Complications included paravaginal abscess (n = 1), postoperative deep venous thrombosis (n = 1), abdominal incision cellulitis (n = 1), and radiation enteritis (n = 1). An open retropubic approach allows direct visualization of the bladder and urethra during interstitial implantation of anterior vaginal malignancies and facilitates negotiation of the pubic arch. In our experience, this technique results in improved needle positioning and is thus intuitively likely to aid in avoiding injury to surrounding normal tissues. Additional accrual of a larger cohort will be necessary to arrive at any meaningful objective conclusions regarding the technique's benefit over current modalities.

Oncogene expression: long-term compared with short-term survival in patients with advanced epithelial ovarian cancer.

OBJECTIVE: To determine if oncogene overexpression in patients with advanced epithelial ovarian cancer correlates with survival. METHODS: Twenty-two women with stage III ovarian cancer, observed for a median of 66 (range 48-204) months were compared with 30 with a median survival of 18 (range 2-28) months. Using immunocytochemistry, tumors were immunostained for overexpression of p53, c-erb-B-2, and epidermal growth factor receptor and were evaluated quantitatively for expression of estrogen receptor, progesterone receptor, and Ki-67 antigen, a marker of cellular proliferation. RESULTS: The median age of long-term survivors was 52 (range 30-76) years compared with 55 (range 36-80) years for short-term survivors. Optimal cytoreduction was achieved in 11 of the 22 long-term survivors compared with seven of the 30 short-term survivors, a significant difference (P=.05). The average level of Ki-67 expression was 43% in long-term survivors and 64% in short-term survivors (P=.007). Overexpression of p53 was seen in 54% of long-term survivors and 80% of short-term survivors (P=.05). A combination of Ki-67 level of 50% or greater plus p53 overexpression was seen in 22% of long-term survivors compared with 68% of short-term survivors (P=.005). Epidermal growth factor receptor, c-erb-B-2, estrogen receptor, and progesterone receptor statuses did not differ significantly between the two groups. CONCLUSION: Markers that did not correlate with survival included the hormone receptors, estrogen receptor and progesterone receptor, and the oncogenes, c-erb-B-2 and epidermal growth factor receptor. Long-term survivors with advanced ovarian cancer were more likely to have had an optimal cytoreduction and lower levels of Ki-67 antigen expression and were less likely to overexpress p53 than were short-term survivors.

Adenocarcinoma of the uterine cervix metastatic to lymph nodes.

OBJECTIVE: We set out to evaluate the prognostic factors in cervical adenocarcinoma metastatic to lymph nodes. STUDY DESIGN: We performed a retrospective review of 40 patients with cervical adenocarcinoma and lymph node metastasis from 1976 to 1996. RESULTS: Thirty-four patients had adenocarcinoma, and six had adenosquamous carcinoma. Median survival was 50 months. The median survival for patients with stage I disease was 69 months. Stage at diagnosis, treatment with radical hysterectomy, and receiving adjuvant therapy were associated with prolonged survival. A trend toward improved survival was noted with the use of concurrent radiation and chemotherapy as an adjuvant therapy. CONCLUSIONS: Adenocarcinoma metastatic to the lymph nodes does not have a uniformly poor prognosis, especially with early-stage disease. Improved survival was observed with the use of adjuvant therapy, specifically the use of combined chemotherapy and radiation after radical hysterectomy. The optimal therapy in this setting is yet to be determined.

The gynecologist's perspective of liability and quality issues with the Papanicolaou smear.

Cytologic screening for precancerous lesions and cancer of the cervix and subsequent treatments of these lesions have been effective in reducing the incidence and mortality of cervical cancer. Gynecologists in the United States have used the concept of an "annual Pap smear exam" to encourage and provide health maintenance medical care for women. Inadvertently, women have been given the perception that Pap smears are highly accurate. Cervical cytology consists of specimen collection and interpretation of the cellular material, with potential errors in either component. The Bethesda System, the most recent classification, was not pretested prior to introduction. Consequently, management guidelines are continuing to evolve. A screening test should only assign a probability of disease in an individual. Ten percent of malpractice lawsuits against pathologists involve misread Papanicolaou smears. Quality improvements have been and should continue to be effective. The liability issue needs to be addressed through public education.

Serum inhibin and disease status in women with ovarian granulosa cell tumors.

OBJECTIVE: To determine if immunoreactive inhibin assayed in serum from women with granulosa cell tumors correlated with tumor burden, reflected response to treatment, or predicted recurrent disease. STUDY DESIGN: Serum samples were collected following bilateral oophorectomy (BSO) with or without other indicated surgery in 15 patients with granulosa cell tumors. Inhibin radioimmunoassay (RIA-Inh) was performed on all samples and results were correlated with tumor burden, disease status, and treatment response. RESULTS: Fifteen patients had serum assayed for inhibin with levels ranging from 0 to 7470 U/liter. In 4 patients with measurable recurrent disease, inhibin levels correlated directly with tumor burden (r2 = 0.96). Four patients had serum drawn during clinical remission and in all 4 patients elevated inhibin levels predated recurrence by a median interval of 11.5 months (range 7-20). The remaining 7 were treated for primary disease and were in clinical remission with a median follow-up of 33 months (range 9-53). Four of these 7 patients were surgically staged: 2 were FIGO Stage I and inhibin levels fell to 0 U/liter; 2 patients had metastatic disease (Stage IIc and IIIa) and their inhibin levels were found to be elevated following complete resection. The remaining 3 were not surgically staged, and all had elevated inhibin levels while in clinical remission, suggesting occult disease. Of the 15 total patients, 1 who was treated with chemotherapy for recurrent disease was followed with serial inhibin levels. She showed a complete response to therapy with inhibin levels falling from 975 to 0 U/liter with 15 months follow-up. CONCLUSIONS: Serum inhibin levels reflect tumor burden and may be valuable in assessing response to chemotherapy or predicting recurrent disease in women with granulosa cell tumors who have had BSO. Serum inhibin level evaluation should be incorporated into large-group trials of therapy for granulosa cell tumors.

Phase II study of high-dose cisplatin, etoposide, and cyclophosphamide for refractory ovarian cancer.

OBJECTIVES: A phase II trial of high-dose cyclophosphamide, etoposide, and cisplatin was done. STUDY DESIGN: Forty-eight patients with progressive or persistent disease and previous cisplatin-based chemotherapy and no paclitaxel therapy were entered for treatment on the basis of two cycles of cyclophosphamide (4500 mg/m2), etoposide (750 mg/m2), and cisplatin (120 mg/m2). RESULT: Seventy-four cycles were delivered. Six patients died during treatment (12.5%). Of 28 with measurable disease, there was a 25% response rate and 32% had stable disease. Median time to recurrence and survival were significantly different for minimal versus bulky disease (p = 0.0089, p = 0.0008, log rank) and for platinum-sensitive versus platinum-resistant disease (p = 0.18, p = 0.0012, log-rank). The number of prior regimens was not correlated with time to progression or survival. CONCLUSION: This study shows little advantage for high-dose protocols except for patients with a response to platinating agents and minimal residual disease.

Expanded pelvic radiotherapy fields for treatment of local-regionally advanced carcinoma of the cervix: outcome and complications.

OBJECTIVE: Recent anatomic and radiographic studies have indicated that standard external beam radiation portals may not adequately treat the volume at risk in patients with local-regionally advanced cervical cancer. A feasibility study was undertaken to evaluate toxicity, outcome, and patterns of failure in patients with advanced cervical cancer treated by expanded pelvic radiation fields. STUDY DESIGN: Thirty-eight women with stages IIB and III cancers of the cervix confined to the pelvis were irradiated with curative intent with expanded pelvic radiation portals. Anteriorly and posteriorly, the median field length and width were 20 and 17.5 cm, respectively. Lateral fields had a median width of 16.5 cm, and the posterior border encompassed the entire sacral silhouette. The median external beam whole-pelvis dose was 4140 cGy, with overall point A dose boosted by brachytherapy to 8315 cGy. RESULTS: Stage IIB patients (n = 22) had a 4-year actuarial local control rate of 70%, freedom from distant metastases rate of 62%, and disease-specific survival rate of 76%. In stage III disease (n = 16), the 4-year actuarial local control, freedom from distant metastases, and disease-specific survival rates were 80%, 48%, and 53%, respectively. Radiographically determined nodal status was an important predictor of disease-specific survival and distant metastases but not local control. The 4-year disease-specific survival rate was 40% in 11 patients with nodal disease compared with 71% in 27 node-negative patients (p < 0.01). The rate of freedom from distant metastases was 36% in node-positive patients versus 67% in node-negative cases (p < 0.01). The actuarial overall 4-year severe late complication rate was 14.8%. CONCLUSION: This study has demonstrated that expanded fields for pelvic radiotherapy is feasible, well tolerated, and therapeutic. The pelvic field design concepts presented should be integrated into radiation oncology practice.

Clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage III disease.

Between 1982 and 1992, 24 women with Stage III clear cell ovarian cancer were identified from the tumor registry. Thirty-four women with Stage III papillary serous tumors treated between 1987 and 1989 were used as a comparison. All patients underwent cytoreductive surgery followed by conventional platinum-based chemotherapy. In the women with clear cell histology, nine (37.5%) had endometriosis in the surgical specimen compared with one (3%) in the papillary serous group (P = 0.002). Ten women (42%) with clear cell histology experienced a thromboembolic event during the course of treatment, compared to six (18%) in the papillary serous group (P = 0.05). In the group with clear cell histology, overall, 70% of women had progressive disease. Fifty-two percent experienced clinical progression while receiving platinum-based chemotherapy. In addition, four patients were found to have progressive disease at second-look laparotomy. Only two patients had a pathologic complete response. In the group with papillary serous histology, 29% overall had progressive disease while on chemotherapy (P = 0.005). The median survival for the women with clear cell histology was 12 months compared to 22 months for those with papillary serous (P = 0.02). For women with clear cell histology, univariate analysis was used to evaluate prognostic factors. Age less than 50 was a poor prognostic factor (P = 0.045). The presence of endometriosis, thromboembolic event, or optimal cytoreduction were not prognostic factors (P = 0.67, P = 0.34, P = 0.39). Patients with advanced clear cell ovarian cancer have a poor response to conventional platinum-based chemotherapy and overall prognosis is poor.

The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma.

Uterine malignant mixed mesodermal tumors (MMMT) are highly malignant tumors containing both malignant glands and stroma, while adenosarcomas (AS) are less aggressive tumors composed of malignant stroma and benign glands. Immunohistochemistry was used to grade overexpression of p53 protein, HER-2/neu protein, epidermal growth factor receptor (EGFR), and Ki-67 antigen in both the glands and stroma of tissue from 20 women with MMMT and 6 women with AS. EGFR was overexpressed in 2 AS and 9 MMMT, and was more commonly found in the sarcomatous component than the carcinomatous component in MMMT (P = 0.03). p53 was not found in any AS samples and was strongly present in 6 MMMT samples with a random distribution between the malignant components. HER-2/neu protein was not overexpressed in any AS or primary MMMT. Ki-67 antigen, a marker of cell proliferation, was found at higher levels in MMMT than AS samples (P = 0.03) and high Ki-67 antigen expression correlated with a decreased survival in patients with MMMT (P = 0.004). Independent characterization of oncogene proteins in the malignant components of these heterogeneous tumors may provide insight into the histogenesis and behavior of these malignancies.

Overexpression and relationships of HER-2/neu, epidermal growth factor receptor, p53, Ki-67, and tumor necrosis factor alpha in epithelial ovarian cancer.

OBJECTIVE: To determine the frequency and possible relationships of overexpression of oncogenes, cytokines, and cellular proliferation proteins in ovarian cancer. METHODS: Sixty-four epithelial ovarian cancer specimens were obtained from the GOG tumor bank. Using immunocytochemistry, tumors were stained for overexpression of HER-2/neu, epidermal growth factor receptor (EGFR), p53, tumor necrosis factor alpha (TNF alpha), and Ki-67 (a marker of cellular proliferation). RESULTS: Twenty-one tumors were Stage I/II and 43 were Stage III/IV. HER-2/neu was overexpressed in 7 cases (11%), EGFR in 12 cases (19%), and p53 in 32 cases (50%). Ki-67 was expressed in all but one case, and high indices (expression in over 50% of cells) were seen in 18 cases (28%). TNF alpha was expressed in all but one case. Comparison between Stage I/II and Stage III/IV cases revealed no difference in the expression of these oncoproteins. Comparison by histologic grade also revealed no difference in the expression of the oncoproteins, except for EGFR, which was overexpressed only in Grade 3 tumors (p = 0.01). Comparison between tumors that did or did not overexpress p53 revealed insignificant differences in the expression of HER-2/neu, EGFR and TNF alpha. In addition there were no differences with respect to stage, grade, or histology when tumors where analyzed with respect to p53 overexpression. There was a trend towards an association between p53 overexpression and high levels of Ki-67 (p = 0.10). Comparison of tumors with high Ki-67 indices to those with lower indices also revealed no association with the expression of HER-2/neu, or EGFR, and there were no differences in stage or grade distribution. CONCLUSION: Ki-67 and p53 were frequently overexpressed in this representative sample of ovarian cancers from the GOG tumor bank; however, their expression was not associated with stage, grade, histology, or overexpression of other oncoproteins. Lack of a recognizable pattern of oncogene overexpression emphasizes the underlying biologic complexity of ovarian cancer.