Hyperthermic intraperitoneal chemotherapy with carboplatin for optimally-cytoreduced, recurrent, platinum-sensitive ovarian carcinoma: a pilot study.

OBJECTIVE: We aimed to evaluate the feasibility and tolerability of hyperthermic intraperitoneal carboplatin (HIPEC-carboplatin) following secondary cytoreduction for recurrent, platinum-sensitive ovarian cancer. METHODS: In a single institution prospective, pilot study, ten patients underwent secondary cytoreductive surgery followed by HIPEC-carboplatin at 1000 mg/m(2). Consolidation (6 cycles) was with platinum-based regimens. Adverse and quality of life were measured throughout treatment. RESULTS: Twelve patients were enrolled of which 2 were excluded (one each for extra-abdominal disease indentified before surgery and suboptimal cytoreduction). All 10 remaining patients received prescribed HIPEC-carboplatin. There were no intra-operative complications or AEs attributable to HIPEC-therapy. Grade 1/2 nausea was the most common post-operative toxicity (6/10 patients). Two patients had grade 4 post-operative neutropenia and thrombocytopenia but only one experienced transient treatment delay. The median hospital stay was 5.5 days. 69/70 (98%) of planned chemotherapy doses were ultimately delivered with 1 patient electively forgoing her final treatment. At a median (range) follow-up of 16 (6-23) months, three patients have recurred at 8, 14, and 16 months from surgery. The median disease-free and overall survivals have not been reached. Fact-O scores were significantly lower following surgery (126 vs. 108, p<.01), but improved by completion of therapy (108 vs. 113, p=0.27). CONCLUSIONS: HIPEC-carboplatin at 1000 mg/m(2) following optimal cytoreduction for ovarian cancer is feasible. Surgical complications were not observed, and post-operative AEs were largely within expected ranges. Consolidation using standard platinum-based regimens was feasible following HIPEC-carboplatin, and preliminary survival data suggests efficacy. Further investigation of HIPEC-carboplatin in the setting of debulkable cancer recurrence is warranted.

A prospective, randomized trial of integrative medicine for women with ovarian cancer.

OBJECTIVES: Despite increased use of integrative medicine in cancer therapy, little data exist on its efficacy. This prospective, randomized, pilot trial sought to evaluate the feasibility of combined modality integrative medicine (CM-IM) in women with ovarian cancer (OvCA) and evaluate its effects on quality of life (QoL), chemotherapy toxicity and immunologic profiles. METHODS: Women with newly diagnosed OvCA requiring chemotherapy were offered enrollment. Those randomized to the experimental arm received hypnosis, therapeutic massage and healing touch with each cycle of chemotherapy. The control arm received chemotherapy without CM-IM. All patients completed QoL questionnaires prior to cycles 1, 3 and 6, and 6-months after chemotherapy. Immunologic profiles were measured. Statistical analysis was based on intent-to-treat. Student's t-test and Fischer's exact-test were used to determine differences. RESULTS: Forty-three women enrolled. All women randomized to CM-IM were successfully treated. There were no statistical differences between the groups in age, stage, grade, histologic cell type, CA125 levels, or surgical cytoreductive status. There was no difference in overall QoL measurements. Re-hospitalization rates, treatment delays, anti-emetic use, and infection rates were similar. Immunologic profiles revealed no difference between arms for WBC or salivary IgA levels. Women receiving CM-IM had consistently higher levels of CD4, CD8 and NK cells, although this did not reach statistical significance. CONCLUSIONS: Prospective clinical evaluation of integrative medicine for women with gynecologic malignancy is feasible. This first, pilot study of CM-IM in gynecologic oncology demonstrated no improvement in QoL or chemotherapy toxicity. Integrative medicine-associated improvements in immunologic profiles warrant further investigation.

Idiopathic Adrenal Hemorrhage in a Patient with Gestational Trophoblastic Neoplasia.

BACKGROUND: Idiopathic unilateral adrenal hemorrhage is rare. Described is the first case reported in the setting of nonmetastatic gestational trophoblastic neoplasia. CASE: A primigravida presented with abdominal pain, fever, and a right upper quadrant mass during the workup for gestational trophoblastic neoplasia. She was diagnosed with idiopathic unilateral adrenal hemorrhage. She was treated with surgical resection and single-agent chemotherapy and had complete remission. CONCLUSIONS: Idiopathic unilateral adrenal hemorrhage is a rare condition and must be considered in the presentation of abdominal pain, fever, and an abdominal mass.

A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a "Sandwich" method for stage III, IV, and recurrent endometrial cancer.

OBJECTIVE: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer. METHODS: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75 mg/m²) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45 Gy)± brachytherapy and three additional cycles of docetaxel and carboplatin. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS). RESULTS: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age=58 years (range: 21-81 years). 78% (32/41)=endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Seven patients died following treatment with a median follow-up of 28 months (range: 7-70 months). KM estimates and 95% confidence intervals for OS at 1 year were 95% (82-99%), at 3 years 90% (75-96%), and at 5 years 71% (45-86%). Of the 39 with primary disease, 11 progressed or died within 5 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 87% (72-94%), at 3 years 71% (51-83%), and at 5 years 64% (42-80%). CONCLUSIONS: "Sandwiching" radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS.

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.

BACKGROUND: Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. METHODS: Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/µL blood 14 days after infusion, based on molecular chimerism and flow cytometry. RESULTS: Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. CONCLUSIONS: Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

Learning about ovarian cancer at the time of diagnosis: video versus usual care.

OBJECTIVE: Effective patient -clinician communication at diagnosis is important, yet decreased provider time for face-to-face interactions makes traditional paradigms in cancer care difficult. We evaluated the effects of an educational video on patients' distress, cancer knowledge, coping skills and attitudes regarding learning about cancer at the time of ovarian cancer diagnosis. METHODS: An educational video was developed in which oncology professionals, women with ovarian cancer, and their relatives discussed cancer information and experiences. Women admitted for initial diagnostic surgical staging for ovarian cancer were randomized to the educational or placebo video. Before and after the video, patients completed measures of (1) ovarian cancer information, (2) emotional distress, (3) learning attitudes, and (4) coping self-efficacy. Outcomes were analyzed for differences in mean change between intervention and placebo groups using t-tests. RESULTS: Fifty-nine subjects were randomized (30 intervention/29 placebo). The majority were advanced staged, white, insured, high school educated, employed, and rated their disease seriousness as high. Anxiety, general distress and cancer-specific distress were high. Pre-post video: distress and self-efficacy between groups were unchanged, intervention subjects answered more knowledge items correctly (p=0.0004) and developed more negative learning attitudes (p=0.037). Following the educational video, patients who developed more negative attitudes also had increased intrusive thinking (p=0.046), a sign of increased distress. CONCLUSIONS: Video presentation of cancer-related information increases learning under conditions of high distress and disease threat however, it is not without risk for some. Differing information needs may affect women's emotional response under these conditions.

Gonadal dysgenesis and gynecologic cancer.

BACKGROUND: Gonadal dysgenesis encompasses a variety of sexual differentiation disorders. Within this population of patients, there is an increased risk of gonadal tumor formation. CASES: In this case series of three patients, two with Swyer's syndrome (complete gonadal dysgenesis) and one with mosaic Turner's syndrome, three separate histologic subtypes of tumors were identified: dysgerminoma, seminoma, and gonadoblastoma. The patients with dysgerminoma and seminoma had regular menses and were without recurrent disease. We recommend that the patient with gonadoblastoma start on hormone therapy. CONCLUSION: Once the diagnosis of gonadal dysgenesis is made, prophylactic gonadectomy should be performed owing to the probability of malignant transformation. These patients illustrate the potential different presentations with gonadal dysgenesis and the importance of complete evaluation of patients with primary amenorrhea.

Outcomes associated with different intraperitoneal chemotherapy delivery systems in advanced ovarian carcinoma: a single institution's experience.

BACKGROUND: Despite increasing use of intraperitoneal chemotherapy the optimal delivery strategy and regimen remain undetermined. Catheter-related complications have been reported in 3-34% of cases across a number of platforms and port styles, but few data compare different catheters directly. We sought to evaluate the complication rate of two separate intraperitoneal chemotherapy port delivery systems used within a single practice. METHODS: We reviewed the medical records of all patients who underwent port placement in our practice (two surgical centers) from January, 2006 through October, 2008. Data extracted included: demographics, medical co-morbidities, port type, timing of placement, intraoperative procedures, reasons for discontinuation of IP chemotherapy, and number of completed cycles. RESULTS: We identified 85 patients who had intraperitoneal ports placed. Four patients were excluded from this analysis: 2 declined chemotherapy and 2 were treated at other institutions and follow-up data was insufficient. Fifty-two (64%) of the 81 patients analyzed had a fenestrated port placed, and 29 (36%) had single lumen ports. In 67 cases (83%) the port was placed at the time of initial cytoreductive surgery. In 14 patients (17%) it was placed as a secondary event. The groups were well matched for age, stage, BMI, and medical co-morbidities though the group with single lumen catheters had more antecedent surgeries. We observed no significant difference between patients with single lumen or fenestrated ports with regard to: number of intraperitoneal treatments, catheter-related complications, hematologic outcomes, and rates of discontinuation. CONCLUSIONS: A low rate of catheter-related complications is observed with both systems. The majority of discontinuations were due to hematologic complications and did not appear to be intrinsic to catheter choice.

A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer.

Objective. The goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Fulvestrant, a novel estrogen receptor (ER) antagonist, has proven clinically beneficial and well-tolerated in treating recurrent breast cancer. Ovarian cancer often expresses ER and may respond to anti-estrogen therapy. We evaluated fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Methods. Patients with ER-positive, multiply recurrent ovarian or primary peritoneal carcinoma and either measurable disease according to RECIST criteria or an abnormal and rising CA-125 were eligible for enrollment. Treatment consisted of single agent fulvestrant, 500 mg IM on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until either intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as CT scans bimonthly. The primary endpoint was clinical benefit (CB=complete response (CR)+partial response (PR)+stable disease (SD)) at 90 days. Results. Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose. Patients had received a median of 5 prior chemotherapeutic regimens (range: 2-13). We observed one CR (4%), one PR (4%), and 9 patients with SD (35%) using modified-Rustin criteria (CA-125 level). Using modified-RECIST criteria 13 patients (50%) achieved SD. The median time to disease progression was 62 days (mean 86 days). Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients). Conclusions. Fulvestrant is well-tolerated and efficacious. Objective response rates are low, but disease stabilization was common.

Gene silencing with siRNA targeting E6/E7 as a therapeutic intervention in a mouse model of cervical cancer.

OBJECTIVE: Selective silencing of HPV oncogenes using short interfering RNA (siRNA) blocks E6/E7 expression and restores normal p53 and Rb function. Our objective was to determine if siRNA targeting E6/E7 would inhibit the growth of established tumors in a mouse model of cervical cancer. METHODS: In vitro studies were performed using unique siRNA sequences to confirm their ability to target and reduce E6/E7 mRNA and restore functioning p53. Next, siRNA targeting lamin was injected daily for three days into tumors established from HPV 16 positive CaSki human cervical cancer cells. Immunohistochemistry and branched DNA gene quantification were used to determine distribution and duration of activity of these siRNA. For our therapeutic studies tumors were directly injected with siRNA targeting E6/E7, non-targeting control siRNA, or saline. In preliminary experiments injections were daily or every three days for a total of three doses. A second therapeutic experiment utilized every three day dosing for 35 days. Tumor volume, growth curves and E7 mRNA levels were assessed. RESULTS: The two most active siRNA sequences resulted in a 67% and 71% reduction in E6/E7 mRNA. Fluorescent lamin siRNA was visualized up to 120 h after the initial tumor injection and was evenly distributed throughout the tumors. IHC showed lamin expression to be inhibited by 68% and 75% when compared to controls at 54 and 120 h respectively. In our preliminary therapeutic intervention experiments there was no significant difference in tumor growth between the treatment groups when mice were treated with three daily injections (p=0.41). However, when treated every third day for three injections final tumor volume was less in animals injected with siRNA sequences A (78% reduction; p<0.0001) and G (60% reduction; p=0.005) compared to saline injection. Tumors showed a corresponding decrease in E6/E7 mRNA. Extended treatment with siRNA completely or nearly eradicated tumors in 70% of the animals. CONCLUSION: Therapeutic siRNA targeting E6/E7 significantly inhibits tumor growth in this mouse model of cervical cancer. Further investigation is needed to determine optimal dosing and route of delivery.

Clinical features and outcomes of uterine and ovarian carcinosarcoma.

BACKGROUND: The objective of this study was to compare the clinical presentation and outcomes of women with ovarian and uterine carcinosarcoma (CS). METHODS: We performed a retrospective review of patients treated for uterine or ovarian CS from 1952 to 2003. Fisher's Exact Test was used to compare patient characteristics. Survival curves were estimated using the Kaplan-Meier method and compared using the log rank test. RESULTS: We identified 87 patients with uterine CS and 18 with ovarian CS. There was no difference in age, body mass index, parity, menopausal status, family history of cancer, history of pelvic radiation, diabetes or hypertension between the two groups. 43% of women with uterine CS presented at stage I/II, compared to 28% of women with ovarian tumors (P = 0.0003). 82% of patients with ovarian tumors received adjuvant chemotherapy with or without radiation; 51% of the patients in the uterine CS group received adjuvant radiation therapy. The median length of follow-up was 13 months. There was no difference in the Kaplan-Meier estimates of overall survival between the two disease sites. The median survival for uterine CS patients was 16 months, compared to 11 months in the ovarian CS group; HR = 0.991 (95% CI = 0.534, 1.839). CONCLUSIONS: We found no differences in patient demographics between the two groups. Despite differences in stage and initial treatment, there was no difference in survival between women with uterine and ovarian CS.

A prospective, randomized study analyzing sartorius transposition following inguinal-femoral lymphadenectomy.

OBJECTIVES: Based on the reduced morbidity seen in our retrospective study, we undertook a prospective, randomized trial to determine whether transposition of the sartorius muscle improves post-operative morbidity in women with squamous cell carcinoma of the vulva undergoing inguinal-femoral lymphadenectomy. METHODS: Patients with squamous carcinoma of the vulva requiring inguinal-femoral lymphadenectomy were randomized to undergo sartorius transposition or not. All patients received perioperative antibiotics, DVT prophylaxis, and closed suction surgical site drainage. Outcomes assessed include wound cellulitis, wound breakdown, lymphocyst formation, lymphedema, and/or rehospitalization. Cohorts were compared using Fisher's exact test. Baseline characteristics were compared using Student's t test or Fischer's exact test as appropriate. Logistic regression was used to assess the impact of sartorius transposition, after adjusting for other factors. RESULTS: From June 1996 to December 2002, 61 patients underwent 99 inguinal-femoral lymphadenectomies, 28 with sartorius transposition, and 33 without. The mean (SD) age for controls and patients undergoing sartorius transposition was 63.5 (15.2) and 73.8 (13.7) years, respectively (P < 0.05). There were no statistically significant differences in BSA, tobacco use, co-morbid medical conditions, past surgical history, medication use, size of incision, duration of surgery, number of positive lymph nodes, pathologic stage, pathologic grade, pre- or postoperative hemoglobin, or length of hospitalization. There were no statistically significant differences in the incidence of wound cellulitis, wound breakdown, lymphedema, or rehospitalization. The incidence of lymphocyst formation was increased in the sartorius transposition group. After adjusting for age, however, the groups appeared similar. CONCLUSIONS: Sartorius transposition after inguinal-femoral lymphadenectomy does not reduce postoperative wound morbidity.