Southwest Oncology Group Trial S9912: intraperitoneal cisplatin and paclitaxel plus intravenous paclitaxel and pegylated liposomal doxorubicin as primary chemotherapy of small-volume residual stage III ovarian cancer.

OBJECTIVE: While primary cisplatin-based intraperitoneal chemotherapy has been shown to favorably impact survival in small-volume residual advanced ovarian cancer, there is a need to develop strategies that improve the effectiveness of this approach. METHODS: A multi-center phase 2 trial was conducted that added intravenous pegylated liposomal doxorubicin (day 8; 30-40 mg/m(2)) to a regimen of intraperitoneal cisplatin (day 2; 75 mg/m(2)) and intravenous (day 1; 135 mg/m(2)) plus intraperitoneal (day 8; 60 mg/m(2)) paclitaxel. Treatment was initially delivered on an every 3-week schedule, but was modified to an every 4-week program due to excessive toxicity. Patients were to receive 6 cycles of this regimen. RESULTS: Of 68 patients entering this trial, 63 patients were eligible and evaluable, of whom 39 (62%) completed 6 cycles. Overall, 32 (51%) experienced at least 1 grade 4 or worse toxicity (most commonly hematologic) including 5 treatment-related deaths. Median progression-free survival (PFS) was 25 months (2-year PFS: 52%) and median overall survival 51 months, an outcome similar to previous reports of cisplatin-based intraperitoneal chemotherapy in comparable patient populations. Seventeen patients (27% of all eligible patients) were without evidence of disease recurrence >4 years following entry into the trial. CONCLUSION: Both the overall trial outcome, and specifically the excessively severe systemic toxicity of this regimen would prevent its future development in this exact form. The provocative PFS in a subset of individuals should encourage the development of alternative strategies designed to optimize the delivery of regional therapy in ovarian cancer management.

Implications of tyrosine phosphoproteomics in cervical carcinogenesis.

BACKGROUND: Worldwide cervical cancer remains a leading cause of mortality from gynecologic malignancies. The link between cervical cancer and persistent infection with HPV has been established. At a molecular level little is known about the transition from the precancerous state to invasive cancer. To elucidate this process, cervical biopsies from human specimens were obtained from precancerous state to stage III disease. METHODS: Cervical biopsies were obtained from patients with a diagnosis of cervical cancer undergoing definitive surgery or staging operation. Biopsies were obtained from patients with precancerous lesions at the time of their excisional procedure. Control samples were obtained from patients undergoing hysterectomy for benign conditions such as fibroids. Samples were subjected to proteomic profiling using two dimensional gel electrophoresis with subsequent trypsin digestion followed by MALDI-TOF protein identification. Candidate proteins were then further studied using western blotting, immunoprecipitation and immunohistochemistry. RESULTS: Annexin A1 and DNA-PKcs were found to be differentially expressed. Phosphorylated annexin A1 was up regulated in diseased states in comparison to control and its level was strongly detected in the serum of cervical cancer patients compared to controls. DNA-PKcs was noted to be hyperphosphorylated and fragmented in cancer when compared to controls. By immunohistochemistry annexin A1 was noted in the vascular environment in cancer and certain precancerous samples. CONCLUSION: This study suggests a probable role for protein tyrosine phosphorylation in cervical carcinogenesis. Annexin A1 and DNA-PK cs may have synergistic effects with HPV infection. Precancerous lesions that may progress to cervical cancer may be differentiated from lesions that will not base on similar immunohistochemical profile to invasive squamous cell carcinoma.

Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: An intergroup study.

OBJECTIVE: Despite the improvement in progression-free and overall survival in patients with advanced ovarian cancer associated with platinum-taxane chemotherapy, strategies are needed to prevent the greater than 70% recurrence rate. METHOD: The Southwest Oncology Group (SWOG) initiated a phase III intergroup trial of alpha-interferon (IFNalpha-26, Schering-Plough, Kenilworth, NJ) in weekly doses of 50 x 10(6) IU (for 6 doses) versus observation only in patients with no pathological evidence of residual disease at second-look surgery in 1988. RESULTS: Patient accrual was extremely slow and the trial was permanently closed in 1999 by the SWOG Data and Safety Monitoring Committee with 74 registered patients. Of these patients, 70 were evaluable for progression-free and overall survival. There was no significant difference between the two study arms in relation to median progression-free survival (P = 0.56). The median survival duration associated with intraperitoneal alpha-interferon had not been reached versus 87 months on the observation arm. In general, intraperitoneal alpha-interferon was well tolerated. There were no treatment-related deaths or grade 4 adverse events. Although no efficacy conclusions can be drawn from this prematurely closed trial, it should be noted that 57% of the patients on the observation arm recurred and all died, whereas 63% recurred and only 43% died on the intraperitoneal alpha-interferon arm. CONCLUSION: Although this was a negative study, there should continue to be interest in the use of biological therapy to improve survival of patients in complete remission following primary chemotherapy.

Recurrent mature cystic ovarian teratoma in adolescence: atypical case of the growing teratoma syndrome.

BACKGROUND: A primary mature cystic ovarian teratoma was diagnosed in an adolescent female. She was followed up after initial exploration with computed tomography, pelvic ultrasonography, and serum tumor markers. Recurrent tumor, consisting solely of mature teratomatous elements, was confirmed with 2 subsequent laparotomies. CASE: This is a report of the growing teratoma syndrome in a young woman with a primary diagnosis of a mature cystic ovarian teratoma not treated with adjuvant chemotherapy. CONCLUSION: The growing teratoma syndrome is an uncommon condition. Surgical resection of recurrent lesions is necessary to reduce potential complications of abdominopelvic organ compression and obstruction and to evaluate for the presence of malignant degeneration.

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group.

OBJECTIVES: To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. METHODS: Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. CONCLUSION: The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.

A patient-centered health care delivery system by a university obstetrics and gynecology department.

At the University of Texas Medical Branch at Galveston, we developed an off-site clinic system that offers a wide array of services to low-income women and their infants over a large geographic area. These clinics strove toward cultural sensitivity and competency. This patient-centered approach was well accepted and appreciated by our patients. The clinics offered unique, value-added services including combined location with other needed services, on-site laboratory and antepartum testing, the option for delivery at the University of Texas Medical Branch at Galveston in a Birth Center by certified nurse midwives from the clinics, 2 high-level ultrasound "hub" centers in the outlying region that offer level II ultrasound and maternal-fetal medicine specialist consultation on site, and linkage of all sites to our electronic medical record, telemedicine, and telegenetics consultation. We also developed an off-site domiciliary facility at the University of Texas Medical Branch at Galveston. From 1989 to 2004, our clinics grew from 12 to 38 (now serving 123 Texas counties). Annual patient visits increased from approximately 34,000 to 342,926. Deliveries at the University of Texas Medical Branch at Galveston grew from 3,959 in 1990 to an estimated 6,400 in 2004. Underscoring this increase was the probable loss of at least 1,500 deliveries to local hospitals that had previously denied or discouraged admission to Medicaid-eligible pregnant women. Many women chose to deliver in our hospital even although they had to travel a longer distance to reach our facility. Our experience has shown that patient-centered care can be a viable business strategy to maintain and expand patient volumes and will work even where there are serious geographic disadvantages.

Primary gastrointestinal cancers presenting as gynecologic malignancies.

OBJECTIVE: The goal of this study was to characterize presenting symptoms, prognostic factors, and treatment outcome in patients diagnosed with primary gastrointestinal (GI) cancers initially presumed to be of gynecologic origin. METHODS: A retrospective review of all admissions to the gynecologic oncology service at Saint Luke's Hospital in Kansas City, Missouri, was performed between 1993 and 2003. Twenty-six patients with primary GI cancers who presented with presumed gynecologic malignancies were identified. Clinical and pathologic features were reviewed, methods of diagnosis were recorded, and survival was analyzed by the Kaplan-Meier method. RESULTS: One percent of all gynecologic cancer referrals had a tumor of nongynecologic gastrointestinal origin. Seven subtypes of GI cancers were identified, most at stage 4 disease. Colon cancer was identified most commonly (26.9%). Abdominal pain was the most frequent symptom (57.6%), and an adnexal mass was diagnosed in the majority of patients (65.4%). Preoperative endoscopic evaluation provided a definitive diagnosis in only 3.8%. The median survival was 15 months with a 5-year survival of 35%. Ninety-six percent of patients had their GI tumor definitively diagnosed by exploratory laparotomy. Optimal cytoreduction provided a 7-month survival advantage. CONCLUSION: Most patients required a major surgical procedure to establish the primary diagnosis of gastrointestinal cancer. The cancers encountered were almost always at advanced stage disease and were referred to the gynecologic oncologist due to the presence of an adnexal mass and a failed preoperative work-up. Surgical management should include removal of the primary or recurrent GI tumor and cytoreduction of all bulky disease, including adnexal metastases.

Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial.

OBJECTIVE: To determine which hydration (saline, saline + mannitol, or saline + furosemide) is associated with least cisplatin nephrotoxicity. METHODS: We randomized 49 women who received cisplatin (75 mg/m(2) every 3 weeks) into one of the three hydration arms. The 24-h creatinine clearance was measured before and on day 6 after cisplatin infusion. The patients of each arm received 2 l of saline hydration. In the saline + furosemide arm, 40 mg of furosemide was given after hydration. In the saline + mannitol arm, 50 g of mannitol was mixed with the cisplatin. RESULTS: For the first cycle of chemotherapy, 15 women were randomized to saline, 17 to saline + furosemide, and 17 to saline + mannitol. For each group, the creatinine clearances before cisplatin infusion were (means+/-SD, milliliters per minute) 84.5+/-26.8, 82.5+/-24.0 and 87.4+/-25.6, and after cisplatin infusion were 79.1+/-31.9, 68.7+/-21.5, and 56.4+/-22.9, respectively. The decreases in creatinine clearance were similar between the saline group and the saline + furosemide group ( P=0.66), but different between the saline + mannitol group and the saline group ( P=0.02) or the saline + furosemide group ( P=0.02). As each woman received multiple courses of cisplatin, 15 who received saline contributed 41 paired datasets, 17 who received saline + furosemide contributed 49 paired datasets, and 17 who received saline + mannitol contributed 36 paired datasets showed similar patterns. CONCLUSIONS: Hydration with saline or saline + furosemide appears to be associated with less cisplatin nephrotoxicity than saline + mannitol.

Combined intraperitoneal and intravenous chemotherapy for women with optimally debulked ovarian cancer: results from an intergroup phase II trial.

PURPOSE: The median survival time for women with optimally debulked adenocarcinoma of the ovary treated with intravenous (IV) chemotherapy is 41 to 52 months, and the 2-year survival rate is 65% to 70%. Recent studies evaluating intraperitoneal (IP) chemotherapy have reported a median survival time of 49 to 63 months and 2-year survival rates of 70% to 80%. This phase II trial was undertaken to evaluate the feasibility of and 2-year survival rate achieved by the combination of IP paclitaxel, IP cisplatin, and IV paclitaxel in women with optimally debulked, stage III ovarian cancer. PATIENTS AND METHODS: Treatment consisted of paclitaxel 135 mg/m(2) IV over 24 hours on days 1 to 2, cisplatin 100 mg/m(2) IP on day 2, and paclitaxel 60 mg/m(2) IP on day 8 administered every 21 days for six cycles. RESULTS: In 68 assessable women with optimal stage III ovarian cancer, the 2-year survival rate was 91%, and the median survival time was 51 months. The 2-year disease-free survival rate was 66%, and median disease-free survival time was 33 months. Ninety-six percent of all patients experienced at least one grade 3 to 4 adverse event during therapy, with the most common events being neutropenia (79%), nausea (50%), vomiting (34%), and fatigue/malaise/lethargy (24%). Seventy-one percent of patients completed all six cycles of IV/IP therapy as planned. CONCLUSION: Combined IV and IP chemotherapy with cisplatin and paclitaxel is associated with a very promising 2-year survival rate in women with optimally debulked ovarian cancer. The ultimate impact of this approach on overall survival requires further evaluation in a randomized trial setting.

Management of atypical glandular cells of undetermined significance pap smears: a reappraisal.

OBJECTIVE.: To find appropriate management of patients with atypical glandular cells of undetermined significance (AGUS) Pap smears. MATERIALS AND METHODS.: The authors present their findings on patients with 606 AGUS Pap smears based on colposcopy, cervical biopsies, endocervical curettage, and endometrial biopsy. Twenty-one proposed management schemes by other authors are reviewed. RESULTS.: From 606 AGUS Pap smears, 69% had benign findings and 31% had neoplastic findings. Among 29 patients with endometrial pathology, only 4 patients (14%) were <40 years old. All proposed management schemes were uniform in the use of colposcopy but differed on the selective use of endometrial biopsy. CONCLUSION.: An AGUS Pap smear requires colposcopy. We suggest endometrial biopsy for women over 40 years old and for women younger than 40 years old who have a high risk for endometrial neoplasia. Better-defined cytologic criteria from cytologists are needed.

Prediction of the need for red cell transfusion in newly diagnosed ovarian cancer patients undergoing platinum-based treatment.

OBJECTIVE: The objective of this study was to develop a predictive algorithm for the likelihood of red blood cell transfusion in women with ovarian cancer undergoing platinum-based chemotherapy. METHODS: Patients in this analysis came from two phase III studies conducted by the Southwest Oncology Group and Gynecologic Oncology Group of platinum-based chemotherapy in advanced ovarian cancer patients, SWOG 8412 and SWOG 8501/GOG 104. The probability of packed red blood cell (PRBC) transfusion was modeled as a function of stage of disease, age, weight, creatinine clearance, hemoglobin (Hb) prior to the start of therapy, the platinum agent administered (i.e., cisplatin vs carboplatin), and the route of drug administration (i.e., intravenous vs intraperitoneal). RESULTS: Overall, 16% of patients developed at least grade 3 anemia (Hb < 8 g/dL) during primary chemotherapy, with 2% experiencing grade 4 anemia (Hb < 6.5 g/dL). PRBC transfusions were administered to 32% of patients. Factors that were determined to be predictive of PRBC transfusions were age and baseline Hb. In patients with bulky stage III or stage IV disease, the odds of transfusion increased by 66% for each 10-year increase in age and by 65% for each 1 g/dL decrease in baseline hemoglobin. Thus a patient aged 65 with a baseline Hb of 10.5 g/dL has approximately a 40% chance of transfusion. CONCLUSIONS: Older ovarian cancer patients (>65 years) with low baseline Hb levels (<10.5) at initiation of platinum-based chemotherapy are likely to become more anemic during treatment and should be considered for prophylactic erythropoietin therapy as an alternative to transfusion.

Using cytology to evaluate the endocervical canal after loop excision.

OBJECTIVE: This study assesses cytology to evaluate the endocervical canal immediately after loop excision. MATERIAL AND METHODS: In 103 patients, we performed a cytologic smear and endocervical curettage immediately after loop excision. Diagnoses were made independently by two cytopathologists and compared to histology. Diagnostic agreement was evaluated statistically. RESULTS: Cytopathologist "A" found a sensitivity of 1.0, specificity of 0.9, positive predictive value (PPV) of 0.44 and negative predictive value (NPV) of 1.0. Cytopathologist "B" found a sensitivity of 0.88, specificity of 0.78, PPV of 0.3 and NPV of 0.98. There was good agreement between the two cytopathologists (kappa = 0.42, 95% CI = 0.25, 0.60). Twenty-five endocervical curettage specimens were insufficient for diagnosis. Seven and 4 cytology specimens were judged unsatisfactory by each cytopathologist, respectively. Histologic and cytologic evaluation charges were $283 and $60.50 per patient, respectively. CONCLUSION: The use of cytology efficiently evaluates the endocervical canal after loop excision.