Transvaginal ureteroneocystostomy.

Ureteral injury is a known complication of gynecologic surgery with potential long-term sequelae. Traditional management of significant ureteral injury recognized at the time of transvaginal pelvic organ prolapse repair is a transabdominal re-implantation procedure using a transabdominal open or laparoscopic approach. We present a case describing a transvaginal approach for ureteroneocystostomy. During a transvaginal pelvic organ prolapse repair, a ureteral transection was noted. A transvaginal ureteroneocystostomy was performed. There was primary healing of the ureteroneocystostomy without sequelae during a 6-month follow-up period.

The clinical and prognostic significance of pre-chemotherapy serum CA-125 in high-risk early stage ovarian cancer: An NRG/GOG ancillary study.

OBJECTIVES: To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4). CONCLUSIONS: Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway.

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.

HIPEC after neoadjuvant chemotherapy is associated with acceptable toxicity and favorable quality of life in newly diagnosed advanced ovarian cancer patients.

OBJECTIVE: To evaluate toxicity, quality of life and PFS in patients with advanced ovarian cancer who underwent neoadjuvant chemotherapy (NAC) followed by CRS and HIPEC with carboplatin. METHODS: Patients with stage IIIC or IVA epithelial ovarian cancer, who were not candidates for primary CRS, were enrolled in this phase two trial. Patients received 3-6 cycles of NAC with an IV carboplatin doublet followed by CRS with HIPEC (carboplatin 800 mg/m2 for 90 min). They were followed for at least 12 months to assess for adverse events, quality of life (QOL) and disease progression. QOL was measured using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaires prior to CRS and post-operatively at 6 weeks, 3 months, and 6 months after CRS. RESULTS: Twenty patients were enrolled. HIPEC was completed successfully in all twenty patients, and there was no peri-operative mortality. Twelve (70.6%) patients experienced a grade 3 or 4 toxicity; most commonly anemia (59%), thrombocytopenia (29%), and hypokalemia (24%). There was no significant change between the pre-operative and postoperative 6 weeks, 3 month, and 6 month FACT-O, NTX, and AD scores. Nine (45%) patients have experienced disease recurrence to date. The median progression free survival in this cohort is 11.2 months (2.5-23.7 months). CONCLUSION: The addition of HIPEC with carboplatin to interval CRS was well tolerated in patient population. Myelosuppression was the most common adverse event. CRS with HIPEC did not adversely impact these patients' QOL indices. The efficacy of this regimen should be further evaluated in a larger clinical trial.

What proportion of patients with stage 3 ovarian cancer are potentially cured following intraperitoneal chemotherapy? Analysis of the long term (≥10 years) survivors in NRG/GOG randomized clinical trials of intraperitoneal and intravenous chemotherapy in stage III ovarian cancer.

OBJECTIVE: Patients with advanced epithelial ovarian cancer (EOC) alive without progression at a landmark time-point of 10 years from diagnosis are likely cured. We report the proportion of patients with Stage III EOC who were long-term disease-free survivors (LTDFS≥10 years) following either intraperitoneal (IP) or intravenous (IV) chemotherapy as well as the predictors of LTDFS. METHODS: Data from 3 mature NRG/GOG trials (104, 114, 172) were analyzed and included demographics, clinicopathologic details, route of administration, and survival outcomes of patients living ≥10 years assessed according to the Kaplan-Meier method. Cox regression survival analysis was performed to evaluate independent prognostic predictors of LTDFS. RESULTS: Of 1174 patients randomized, 10-year overall survival (OS) was 26% (95% CI, 23-28%) and LTDFS ≥10 years was 18% (95% CI, 16-20%). Patients with LTDFS ≥10 years had a median age of 54.6 years (p < 0.001). Younger age (p < 0.001) was the only independent prognostic factor for LTDFS≥10 years on multivariate Cox analysis. CONCLUSIONS: Approximately 18% of patients were LTDFS ≥10 years. They form the tail end of the survival curve and are likely cured. Our results provide a comparative benchmark to evaluate the impact of PARP inhibitors in 1st line maintenance trials on survival outcomes.

Predicting the return of bladder function following vaginal native tissue repair using data from a suprapubic catheter regimen.

AIMS: To evaluate time to return of normal voiding function following native tissue vaginal reconstruction and evaluate risk factors for postoperative urinary retention (POUR). METHODS: A retrospective cohort analysis of women undergoing vaginal reconstruction and suprapubic catheter with standardized regimen for voiding trials. Postvoid residual <150 ml at 4 h post catheter clamping was used as surrogate marker for return of bladder function. Univariate and multivariate regression analyses were used to identify risk factors for return of bladder function >4 days after surgery. RESULTS: Between 2013 and 2018, 148 women underwent surgery, 124 were analyzed. Mean age was 67 years (±11.1), 62.9% (n = 78) had greater than or equal to stage 3 prolapse. Mean time to return of bladder function: 4.1 days (±3.1). Significant risk factors for >4 days to return of bladder function on univariate analysis included (mean ± SD): surgery length (150.4 min ±44.6) (odds ratio [OR], 1.24; confidence interval [CI], 1.12, 1.38); anesthesia length (228.1 min ±53.5) (OR, 1.12; CI: 1.04, 1.23); length of stay (2.2 days ±2.7) (OR, 2.43; CI: 1.11, 5.35); hysterectomy (OR, 3.10; CI: 1.39, 6.90); estimated blood loss (124.4 ml ±64.8) (OR, 1.39; CI: 1.04, 1.87). Postmenopausal status was protective (OR, 0.17; CI: 0.03, 0.92.). On multivariate analysis, significant findings were diabetes mellitus (OR, 0.18; CI: 0.04, 0.93) and surgery length (OR, 1.21; CI: 1.06, 1.38). CONCLUSIONS: Hysterectomy, surgical length and estimated blood loss were significantly associated with delayed return of bladder function after native tissue vaginal reconstruction. This data can help clinicians tailor postoperative voiding trials after failed initial attempt.

Serum Calcium and Serum Albumin Are Biomarkers That Can Discriminate Malignant from Benign Pelvic Masses.

BACKGROUND: Biomarkers that aid in the differential diagnosis of malignant pelvic masses from benign ones prior to surgery are needed in order to triage women with malignant masses to appropriate specialist care. Because high albumin-adjusted serum calcium predicted ovarian cancer among women without evidence of disease, we hypothesized that it might predict cancer among women with pelvic masses that were evident radiographically. METHODS: We studied a cohort of 514 women with pelvic masses who underwent resection at Wake Forest University Baptist Medical Center from July 2009 through June 2013. We divided patients into a "training" set, to identify associations in the data, and a "testing" set, to confirm them. Data were obtained from medical records. A best fit model was selected using the Akaike Information Criterion. RESULTS: Albumin-adjusted serum calcium was significantly higher in women with malignant versus benign masses (P = 0.0004). High normocalcemia, i.e., an albumin-adjusted serum calcium ≥ 10 mg/dL, occurred in 53% of women with malignant tumors versus 12% of benign tumors. High normocalcemia was associated with an approximately 14-fold increased risk of malignancy. The best fit model (Overa) included albumin, calcium, and nonlinear terms. Overa achieved an area under the curve of 0.83 with a sensitivity of 72% and specificity of 83%, a positive predictive value of 71% and a negative predictive value of 85%. CONCLUSIONS: A model using serum calcium and serum albumin to predict malignancy in women with pelvic masses has high sensitivity and is economical. IMPACT: Our model can help triage women with ovarian cancer to appropriate surgical care.

Catumaxomab for the treatment of malignant ascites in patients with chemotherapy-refractory ovarian cancer: a phase II study.

OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites. METHODS: The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 µg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc. RESULTS: Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance. CONCLUSIONS: Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action.

Is bilateral lymphadenectomy for midline squamous carcinoma of the vulva always necessary? An analysis from Gynecologic Oncology Group (GOG) 173.

OBJECTIVE: To determine which patients with near midline lesions may safely undergo unilateral groin dissection based on clinical exam and lymphoscintigraphy (LSG) results. METHODS: Patients participating in GOG-173 underwent sentinel lymph node (SLN) localization with blue dye, and radiocolloid with optional LSG before definitive inguinal-femoral lymphadenectomy (LND). This analysis interrogates the reliability of LSG alone relative to primary tumor location in those patients who had an interpretable LSG and at least one SLN identified. Primary tumor location was categorized as lateral (>2cm from midline), midline, or lateral ambiguous (LA) if located within 2cm, but not involving the midline. RESULTS: Two-hundred-thirty-four patients met eligibility criteria. Sixty-four had lateral lesions, and underwent unilateral LND. All patients with LA (N=65) and midline (N=105) tumors underwent bilateral LND. Bilateral drainage by LSG was identified in 14/64 (22%) patients with lateral tumors, 38/65 (58%) with LA tumors and in 73/105 (70%) with midline tumors. At mapping, no SLNs were found in contralateral groins among those patients with LA and midline tumors who had unilateral-only LSGs. However, in these patients groin metastases were found in 4/32 patients with midline tumors undergoing contralateral dissection; none were found in 27 patients with LA tumors. CONCLUSION: The likelihood of detectable bilateral drainage using preoperative LSG decreases as a function of distance from midline. Patients with LA primaries and unilateral drainage on LSG may safely undergo unilateral SLN.

Lymphatic mapping and sentinel lymph node biopsy in women with squamous cell carcinoma of the vulva: a gynecologic oncology group study.

PURPOSE: To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer. PATIENTS AND METHODS: Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed. RESULTS: In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%). CONCLUSION: Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.

Outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface dissemination from ovarian neoplasms.

BACKGROUND: Few data exist on the treatment of peritoneal surface dissemination (PSD) from ovarian cancer (OC) with hyperthermic intraperitoneal chemotherapy (HIPEC). This work represents a review of the authors' institution's experience with HIPEC for PSD from OC. METHODS: Fifty-one patients with OC treated with HIPEC between 1996 and 2009 were identified in a prospectively managed database. All patients underwent maximal tumor debulking followed by HIPEC with mitomycin C, carboplatin, or paclitaxel. RESULTS: The median survival in this cohort was 29 months. When stratified by resection status, patients undergoing R0 and R1 resections experienced longer median survival than those who underwent R2 resections (47 vs 12 months, P = .0002). Intraoperative blood loss ≤ 400 mL resulted in greater 5-year survival than blood loss > 400 mL (60% vs 15%, P = .025). CONCLUSIONS: This experience demonstrates that long-term survival is anticipated in patients who undergo complete cytoreduction followed by HIPEC for PSD from OC. These findings not only highlight the potential utility of HIPEC in the treatment of OC but also underscore the importance of maximal cytoreduction followed by HIPEC in this cohort of patients.

A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study.

BACKGROUND: Nab-paclitaxel is a novel Cremophor®-free nanoparticle of albumin-stabilized paclitaxel, which has favorable efficacy and toxicity characteristics relative to other solvent-based taxanes, such as paclitaxel and docetaxel. METHODS: Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n = 5) or recurrence within 6 months of treatment completion (n = 42). All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of ≤ 2. Treatment was nab-paclitaxel, 100 mg/m² days 1, 8, and 15 on a 28-day schedule. The primary endpoint was Response Evaluation Criteria in Solid Tumors v1.0 response rate, evaluated in a 2-stage design (with power of 0.90 for a RR of 25% and with alpha of 0.05 for RR of 10%). RESULTS: Fifty-one patients were enrolled of which 47 were evaluable; median time from frontline therapy completion to registration was 21 days. Patient demographics include median age: 59 (34-78) years, serous histology: 72%, and high-grade: 81%. EFFICACY: one complete and 10 partial responses were confirmed (23%); 17 patients (36%) had stable disease. The median progression-free survival was 4.5 months (95% CI: 2.2-6.7); overall survival was 17.4 months (95% CI: 13.2-20.8). Seventeen patients (36%) had PFS > 6 months. TOXICITY: there were no grade 4 events; grade 3 events were neutropenia (6), anemia (3), GI (2), metabolic (2), pain (2), and leukopenia (1); neurosensory toxicity was observed as grade 2:5, grade 3:1. CONCLUSIONS: Nab-paclitaxel has noteworthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.

A phase II study of two topotecan regimens evaluated in recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer: a Gynecologic Oncology Group Study (GOG 146Q).

OBJECTIVE: To evaluate the efficacy and safety of topotecan in patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas. METHODS: A randomized phase II analysis of platinum-sensitive patients with measurable disease was performed independently assessing intravenous topotecan 1.25 mg/m2 daily×5 every 21 days (regimen I) and topotecan 4.0 mg/m2/day on days 1, 8, and 15 of a 28-day cycle (regimen II). All patients were treated until disease progression, unmanageable toxicity, or patient refusal. Insufficient accrual related to regimen I resulted in a redesign of the study as a single arm phase II trial assessing only regimen II. More complete efficacy data is presented for regimen II as enrollment on regimen I was insufficient for some analyses. RESULTS: A total of 81 patients were enrolled. One patient was ineligible. Fifteen patients received regimen I, while 65 patients were treated with regimen II. The response rate on regimen I (daily×5) was 27% (90% CI: 10-51%) and 12% (90% CI: 6-21%) on regimen II (weekly). The median PFS and OS were 4.8 and 27.8 months, respectively, for regimen II. Grade 3/4 neutropenia rate was 93% with daily×5 dosing and 28% for weekly treatment. Febrile neutropenia was very low in both groups. CONCLUSION: The weekly regimen of topotecan appeared less active but resulted in less toxicity than the daily regimen in platinum-sensitive recurrent ovarian cancer patients.

Intraperitoneal hyperthermic chemotherapy using carboplatin: a phase I analysis in ovarian carcinoma.

OBJECTIVE: Cyclic platinum-based intraperitoneal chemotherapy has proven to be effective after optimal surgical cytoreduction in ovarian carcinoma. Hyperthermia is directly cytotoxic and enhances chemotherapy tumoricidal effects. This study was designed to determine the maximum tolerated dose (MTD) of carboplatin used intraoperatively as intraperitoneal hyperthermic chemotherapy (IPHC), the effect on postoperative systemic chemotherapy administration, and the potential for repeat IPHC at second look surgery. METHODS: Using the ThermoChem HT System, escalating doses of carboplatin (400, 600, 800, 1000, and 1200 mg/m(2)) were administered intraoperatively as IPHC with a perfusion time of 90 min. A subgroup of eight patients that received initial IPHC and subsequent systemic chemotherapy underwent second look reassessment surgery with IPHC. RESULTS: The first 4 dose levels were well tolerated without dose-defining toxicity. The initial two patients treated at 1200 mg/m(2) developed grade 4 myelosuppression thus defining the MTD at 1000 mg/m(2). Newly diagnosed ovarian cancer patients receiving the initial IPHC at the MTD defined above completed standard systemic chemotherapy with six courses of systemic chemotherapy. Eight patients having initial IPHC and systemic chemotherapy subsequently had repeat IPHC performed at second look laparotomy without grade 3 or 4 toxicities. Four patients were found to have extensive adhesions at the time of second look reassessment surgery yet completed IPHC. CONCLUSIONS: The MTD for intraperitoneal carboplatin administered as IPHC was established at 1000 mg/m(2). IPHC at the initial cytoreductive procedure did not preclude subsequent systemic chemotherapy. In addition, repetitive IPHC was feasible at second look reassessment surgery.

A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study.

PURPOSE: To investigate, in a phase III randomized trial, whether postoperative external-beam irradiation to the standard pelvic field improves the recurrence-free interval and overall survival (OS) in women with Stage IB cervical cancers with negative lymph nodes and certain poor prognostic features treated by radical hysterectomy and pelvic lymphadenectomy. METHODS AND MATERIALS: Eligible patients had Stage IB cervical cancer with negative lymph nodes but with 2 or more of the following features: more than one third (deep) stromal invasion, capillary lymphatic space involvement, and tumor diameter of 4 cm or more. The study group included 277 patients: 137 randomized to pelvic irradiation (RT) and 140 randomized to observation (OBS). The planned pelvic dose was from 46 Gy in 23 fractions to 50.4 Gy in 28 fractions. RESULTS: Of the 67 recurrences, 24 were in the RT arm and 43 were in the OBS arm. The RT arm showed a statistically significant (46%) reduction in risk of recurrence (hazard ratio [HR] = 0.54, 90% confidence interval [CI] = 0.35 to 0.81, p = 0.007) and a statistically significant reduction in risk of progression or death (HR = 0.58, 90% CI = 0.40 to 0.85, p = 0.009). With RT, 8.8% of patients (3 of 34) with adenosquamous or adenocarcinoma tumors recurred vs. 44.0% (11 of 25) in OBS. Fewer recurrences were seen with RT in patients with adenocarcinoma or adenosquamous histologies relative to others (HR for RT by histology interaction = 0.23, 90% CI = 0.07 to 0.74, p = 0.019). After an extensive follow-up period, 67 deaths have occurred: 27 RT patients and 40 OBS patients. The improvement in overall survival (HR = 0.70, 90% CI = 0.45 to 1.05, p = 0.074) with RT did not reach statistical significance. CONCLUSIONS: Pelvic radiotherapy after radical surgery significantly reduces the risk of recurrence and prolongs progression-free survival in women with Stage IB cervical cancer. RT appears to be particularly beneficial for patients with adenocarcinoma or adenosquamous histologies. Circumstances that may have influenced the overall survival differences are considered.

Transvaginal repair of the posthysterectomy vesicovaginal fistula using a peritoneal flap: the gold standard.

OBJECTIVE: To evaluate the transvaginal approach to management of vesicouterine fistulas. STUDY DESIGN: Over a 10-year period, 7 cases of simple posthysterectomy vesicovaginal fistulas were identified. The surgical technique involved resection of the fistulous tract completely, performance of layered closure and placement of a peritoneal flap between the bladder and vaginal suture lines. RESULTS: One fistula closed spontaneously, and the remaining 6 were repaired transvaginally. Primary repair was successful in all cases, with no complications. CONCLUSION: The transvaginal repair described is the preferred method of repair, associated with an extremely high success rate, low morbidity and cost savings. Its approach should be considered the gold standard.

Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study.

OBJECTIVES: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen. METHODS: Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity. RESULTS: Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity. CONCLUSION: Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Adjuvant therapy of completely resected dysgerminoma with carboplatin and etoposide: a trial of the Gynecologic Oncology Group.

OBJECTIVE: This study was designed to evaluate the effect of adjuvant chemotherapy with carboplatin and etoposide in patients with completely resected stage IB-III dysgerminoma. METHODS: Eligible patients were treated with three courses of carboplatin 400 mg/m(2) on day 1 plus etoposide 120 mg/m(2) on days 1, 2, and 3 every 4 weeks for three courses. RESULTS: Forty-two patients were entered on this trial, of whom 39 were eligible. No patient suffered a recurrence of dysgerminoma, but one patient ultimately died of lung adenocarcinoma. One patient was excluded on pathology review (elements of endodermal sinus tumor were present) developed recurrent tumor and died despite further therapy. As expected, the regimen was well tolerated. Median follow-up of surviving patients is 7.8 years (range: 2.86 months to 10.92 years). CONCLUSION: The regimen used in this study is an alternative to cisplatin, etoposide, and bleomycin (BEP) for selected patients for whom minimizing toxicity (particularly neuropathy) is critical or for whom reduction in the number of treatment days is important.

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. METHODS: Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given. RESULTS: Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17-38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors (n = 16), 24% in those with grade 2 disease (n = 17), and 22% among patients with grade 3 disease (n = 23). Women less than or equal to 60 years (n = 16) appear to have a better response rate than those >60 years (n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease (n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease (n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. CONCLUSION: A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.