Gregory P. Sutton

Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study.

PURPOSE To assess progression-free survival (PFS) and overall survival (OS) in patients with suboptimally debulked epithelial ovarian cancer receiving cisplatin (100 mg/m(2)) or 24-hour infusion paclitaxel (200 mg/m(2)) or the combination of paclitaxel (135 mg/m(2)) followed by cisplatin (75 mg/m(2)). PATIENTS AND METHODS After stratification for disease measurability, patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS Six hundred fourteen of 648 patients who entered onto the trial were eligible. Monotherapies were discontinued more frequently (cisplatin because of toxicity or patient refusal [17%], and paclitaxel because of progression [20%]) compared with the combination therapy (7% and 6%, respectively). Neutropenia, fever, and alopecia were more severe with paclitaxel-containing regimens; whereas anemia, thrombocytopenia, neurotoxicity, nephrotoxicity, and gastrointestinal toxicity were more severe with cisplatin-containing regimens. The CR/PR rates on paclitaxel monotherapy were significantly lower compared with the cisplatin regimens (42% v 67%, respectively; P <.001). The relative hazard (RH) of first progression or death was significantly greater among those randomized to paclitaxel (RH = 1.41; 95% confidence interval [CI], 1.15 to 1.73; P <.001) when compared with cisplatin; however, RH did not differ significantly between the two cisplatin regimens (RH = 1.06; 95% CI, 0.895 to 1.30). Relative to cisplatin, the death rate on paclitaxel was 15% greater (RH = 1.15; 95% CI, 0. 929 to 1.42), and the death rate on the combination treatment was 1% less (RH = 0.99; 95% CI, 0.795 to 1.23). These differences among treatment groups were not statistically significant (P =.31). CONCLUSION Cisplatin alone or in combination yielded superior response rates and PFS relative to paclitaxel. However, OS was similar in all three arms, and the combination therapy had a better toxicity profile. Therefore, the combination of cisplatin and paclitaxel remains the preferred initial treatment option.

Abdominal sacral colpopexy with Mersilene mesh in the retroperitoneal position in the management of posthysterectomy vaginal vault prolapse and enterocele

During a 12-year study period from 1972 to 1984, 56 patients underwent abdominal sacral colpopexy with retroperitoneal interposition of a suspensory hammock between a prolapsed vaginal vault and the anterior surface of the sacrum. They were followed from 6 months to 12 1/2 years, and constitute the basis of this report. In most patients, a synthetic mesh was the material interposed. Hysterectomy had previously been performed on 53 patients, and in two patients there was congenital absence of the uterus. Indications for abdominal sacral colpopexy, surgical technique, complications, and results of operation are discussed. Seven additional patients underwent this operation after termination of the defined study period.

Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study.

Surgical and pathologic findings at laparotomy for radical hysterectomy in 990 patients with clinical stage IB carcinoma of the cervix were analyzed to determine the frequency of metastases to the ovary. Ovarian spread was identified in 4 of 770 (0.5%) patients with squamous carcinoma and 2 of 121 (1.7%) with adenocarcinoma. No patients with adenosquamous carcinoma (n = 82) or other histologic types (n = 17) had ovarian metastases. Although the frequency of metastases was greater among patients with adenocarcinoma, this was not statistically significant (p = 0.19, Fishers exact test). All 6 patients with ovarian metastases had other evidence of extracervical disease. Three underwent radical hysterectomy and bilateral salpingo-oophorectomy. Of these, one patient received extended field radiotherapy and died of disease 18 months after diagnosis. Two patients, one treated with combination chemotherapy and one with no adjunctive therapy, are alive without evidence of disease at 59 and 62 months, respectively. Three patients underwent exploratory laparotomy with salpingo-oophorectomy and lymphadenectomy without hysterectomy. All three patients died of disease at 2, 3, and 30 months; the first and last patient received adjunctive radiotherapy. Not all patients underwent oophorectomy. Of 347 patients with at least unilateral ovarian preservation, no postoperative pelvic radiotherapy, and no gross extracervical disease or metastasis to the paraaortic nodes, pelvic recurrence developed in 16. There was no excess of pelvic recurrences in patients with adenocarcinoma (0/41) or adenosquamous carcinoma (1/29, 3.4%) when compared with those with squamous carcinoma (15/270, 5.6%). This suggests no excess of occult ovarian metastases in nonsquamous tumors of the cervix. There is no evidence in these data of an increased risk of ovarian preservation in patients with stage IB carcinoma of the cervix with no gross extracervical disease.

Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: A study of the gynecologic oncology group

Objective To determine the effectiveness and toxicity of ifosfamide chemotherapy in women with metastatic or recurrent endometrial stromal sarcomas unexposed to other chemotherapy. Methods In a prospective, multi-institutional phase II study conducted by the Gynecologic Oncology Group, the starting dose of ifosfamide was 1.5 g/m2 given daily intravenously (IV) for 5 days (reduced to 1.2 g/m2 daily in patients who had previously received radiotherapy). Mesna (2-mercaptoethane sodium sulfonate) was given IV immediatley and at 4 and 8 hours after the administration of ifosfamide. EAch dose of mesna was 20% of the total daily dose of ifosfamide. Patients were treated every 3 weeks if blood counts permitted. Therapy was discontinued if there was progression of the cancer or unacceptable toxicity. Results Twenty-two patients were entered into this study. One was excluded from analysis because of the wrong histologic type, leaving 21 evaluable for response and toxicity. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in four patients (19%), and one patient each experienced Gynecologic Oncology Group grade 4 anemia and genitourinary toxicity. Three patients experienced complete tumor responses and four had partial responses, for an overall response rate of 33.3%. Conclusion Ifosfamide is active in the therapy of women with chemotherapy-naive metastatic or recurrent endometrial stromal sarcomas.

Endocrine changes at operation under general anesthesia: reproductive hormone fluctuations in young women.

This study investigated changes in peripheral serum estrogen (E), Progesterone (P), luteinizing hormone (LH), follicle-stimulating hormone, and prolactin (PRL) in 11 women of reproductive age undergoing a variety of operations under general anesthesia without compromise of ovarian vasculature. All hormone determinations were plotted in relation to the midcycle LH peak; eight women with cyclic ovulatory menses served as controls. The absolute value of E declined after surgery but did not reach statistical significance. P levels postoperatively were significantly lower following ovulation (P less than 0.01) on cycle days +1 through +5. Intraoperative and postoperative PRL values were significantly greater than those of control subjects (P less than 0.05). Aside from a transient intraoperative decline in LH, the pattern of gonadotropin secretion was similar to that of control subjects. The decline in peripheral ovarian steroid levels appeared to be independent of abdominal entry or pelvic manipulation. The evidence favors direct inhibition of ovarian steroidogenesis by (1) toxic effects of anesthetic agents or (2) stress-induced changes in other hormone levels, e.g., hyperprolactinemia.

Trends in the operative management of invasive squamous carcinoma of the vulva at Indiana University, 1974 to 1988

From January 1974 to March 1988, 150 patients with primary invasive squamous cell carcinoma of the vulva underwent surgery at Indiana University. There has been a trend toward more conservative surgical management of this disease. To determine the impact of this trend on clinical outcome, cases were divided into three groups according to date of operation: group I, 1974 to 1978; group II, 1979 to 1983; and group III, 1984 to 1988. Overall, 80 patients had en bloc radical vulvectomy and groin dissection, 20 had modified radical vulvectomy and bilateral groin dissection through three separate incisions, and 36 had modified radical vulvectomy and unilateral superficial groin dissection. Fourteen patients had other operations. Forty-two patients (27.3%) had radiotherapy in addition to surgery. Among the three groups, there were no differences when mean age, International Federation of Gynecology and Obstetrics stage distribution (1988 system), mean lesion size, mean depth of invasion, or grade distribution were compared. A significant trend toward more conservative surgical therapy was observed. En bloc radical vulvectomy was performed in 77.4% of group I patients, 71.1% of group II patients, and 35.8% of group III patients (p less than 0.001). Mean days of hospitalization were also reduced significantly. Group I had a mean stay of 30 days, group II had a mean stay of 23 days, and group III had a mean stay of 11 days (p less than 0.001). Mean operative blood loss (group I, 754.8 ml; group II, 620.0 ml; group III, 393.6 ml; p = 0.03), mean units of blood transfused (group I, 1.4 units; group II, 1.3 units; group III, 0.4 units; p less than 0.01), and mean hours of operating time (group I, 3.7 hours; group II, 3.7 hours; group III, 3.2 hours; p = 0.02) were also reduced.

Phase II Evaluation of Dalantercept, a Soluble Recombinant Activin Receptor-Like Kinase 1 (ALK1) Receptor Fusion Protein, for the Treatment of Recurrent or Persistent Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study 0229N

OBJECTIVE This two-stage phase II study assessed activity of single agent dalantercept in patients with recurrent/persistent endometrial carcinoma (EMC). METHODS Eligible patients had persistent/recurrent EMC after 1-2 prior cytotoxic regimens, measurable disease (RECIST 1.1), and GOG performance≤2. Dalantercept 1.2mg/kg subcutaneous was administered once every 3weeks until disease progression (PD)/development of prohibitory toxicity. Primary objectives were to estimate the proportion of patients with persistent/recurrent EMC, who survive progression-free without receiving non-protocol therapy (TPFS) for at least 6months and to estimate the proportion having objective tumor response. RESULTS All 28 enrolled patients were eligible and evaluable. Median age: 62years. Most common histologies: 32% Grade 1/2 endometrioid and 54% serous tumors. Prior treatment: 1 or 2 regimens in 82% and 18% of patients, respectively. Eighteen patients received prior radiation therapy. Patients received 1-12 cycles of dalantercept, and 46% of patients received ≤2cycles. The most common adverse events (AE) were fatigue, anemia, constipation and peripheral edema. Grade 3/4 AEs occurred in 39% and 4% of patients. One grade 5 gastric hemorrhage in a patient with a history of radiation fibrosis/small bowel obstruction was deemed possibly dalantercept-related. All patients are off study: 86% for PD. No ORs were observed; 57% had stable disease and 11% had TPFS>6 mos. Median progression-free and overall survival: 2.1months (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.0-17.5), respectively. CONCLUSIONS Dalantercept has insufficient single agent activity in recurrent EMC to warrant further investigation at this dose level and schedule.

Estrogen and progesterone receptors in epithelial ovarian malignancies

Cytoplasmic estrogen receptor levels (ER) were measured in ovarian epithelial malignancies from 44 patients using a dextran-coated charcoal assay with analysis of the data by Scatchard plots. In 31 cases, progesterone receptor levels (PR) were also determined. In untreated patients, 68.8% of malignancies were ER-positive (greater than or equal to 10 fmole receptor/mg protein) and 35.0% were PR-positive (greater than or equal to 50 fmole/mg protein). Receptor levels in ovarian epithelial malignancies were not dependent on patient age, menopausal status, tumor stage, or histologic grade. However, ovarian endometrioid carcinomas contained significantly more PR than other histologic variants (P less than 0.02). Excluding endometrioid carcinoma, tissues from patients treated with chemotherapy contained less ER and PR than tissues from untreated patients. ER-positive tumors from three patients assayed before cyclophosphamide or combination chemotherapy became ER-negative after therapy. In addition, tamoxifen increased cytoplasmic PR (124 to 333 fmol/mg) and decreased cytoplasmic ER (65 to 4 fmol/mg) in a single patient with endometrioid carcinoma.

Uterine sarcomas 2013

Sarcomas comprise approximately 5–6% of the 49,560 cases of uterine cancer occurring in the United States in 2013 [1]; the contribution of these cases to the projected 8190 annual deaths, however, approaches 30% [2]. Although there is an extensive classification of these tumors, this review is limited to carcinosarcomas, leiomyosarcomas, endometrial stromal sarcomas, and mullerian adenosarcomas. Carcinosarcomas probably represent dedifferentiated endometrial adenocarcinomas, but they will be included. It is critical to the understanding of thesemalignancies to distinguish among them. Since they are rare tumors, they are often combined in clinical reviews [3], leading to confusion in the understanding of individual types. Carcinosarcomas and leiomyosarcomas, the most common stromal tumors, are readily differentiated clinically. Exposure to tamoxifen [4] or radiation therapy [5] is a risk factor for carcinosarcomas; leiomyosarcomas rarely spread to lymph nodes [6] and are resistant to cisplatin [7]; age at diagnosis is typically around 50 years for leiomyosarcomas and the mid 60s for carcinosarcomas [8]. Leiomyosarcomas are commonly diagnosed pathologically after hysterectomy, and carcinosarcomas are diagnosed at the time of endometrial biopsy or curettage for bleeding. Carcinosarcomas occur disproportionately often in African-American females [9]. Carcinosarcomas should be staged as carcinomas of the endometrium. Staging for leiomyosarcomas, endometrial stromal tumors, and mullerian adenosarcomas is represented in Fig. 1, 2009 FIGO staging [10]

A phase II study of gemcitabine, carboplatin and bevacizumab for the treatment of platinum-sensitive recurrent ovarian cancer

PURPOSE The doublet gemcitabine and carboplatin is effective for the treatment of recurrent ovarian cancer, while multi-agent chemotherapy with bevacizumab may add additional benefit. This phase II study tested the efficacy and safety of a biweekly gemcitabine, carboplatin, and bevacizumab combination in patients with platinum-sensitive recurrent ovarian, peritoneal, or tubal cancer (ROC). PATIENTS AND METHODS Eligible patients received concurrent gemcitabine 1000 mg/m(2), carboplatin area under the curve 3, and bevacizumab 10 mg/kg administered intravenously on days 1 and 15 every 28 days for six cycles or up to 24 cycles if clinical benefit occurred. The primary end points were progression-free survival (PFS) by RECIST, and safety; the secondary end points were objective response rates and overall survival. RESULTS Overall, 45 patients were enrolled. The median PFS was 13.3 months (95% CI, 11.3 to 15.3). The objective response rate was 69%. Grade 4 hematologic toxicities included neutropenia (27%) and thrombocytopenia (2%). Grades 3 and 4 non-hematologic toxicities included fatigue (18%), pain (9%), and nausea/vomiting (4%). There were 2 episodes of cerebrovascular accidents, 2 noted DVTs, and no episodes of bowel perforation. Median OS was 36.1 months (95% CI, 26.7 to 45.5). CONCLUSION Biweekly gemcitabine, carboplatin, and bevacizumab were an effective regimen in recurrent ovarian cancer, with comparable toxicity to recently reported day 1 gemcitabine, carboplatin, bevacizumab, and day 8 gemcitabine. Response rate and PFS are improved from reported outcomes of the gemcitabine carboplatin doublet. The degree to which biweekly dosing may present a more rationale schedule for this triplet should be evaluated further.