Amy L. Jonson

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.

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.

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 Swyers syndrome (complete gonadal dysgenesis) and one with mosaic Turners 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.

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.

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 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. Students t-test and Fischers 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.

Abstract 1377: Guided imagery use in the peri-operative period of gynecologic oncology surgery.

Objective: To assess the feasibility of using guided imagery therapy in the peri-operative period at the time of Gynecologic Oncology surgery. Methods: IRB approval was obtained for this randomized control trial. Patients were recruited based on having an exploratory laparotomy surgery with the gynecologic oncology group. Research staff performed a phone interview and obtained written consent. Patients were randomized to standard of care therapy, blank CD which was to simulate noise reduction headphones, or a validated guided imagery CD. The intervention would be used in pre op waiting area, during surgery, and after surgery. VAS scores, amount of narcotics used, amount of anti-emetics used, FACT G and POMS surveys were collected. Results: 12 patients were attempted to be recruited for the study from April 2012 to the present. Prior to study enrollment, all patients were excited about the study and willing participants. All 12 pre op nurses were a barrier to discuss the study with the patients in the pre op area. 2 patients were unable to be consented due to the pre-operative nursing staff baring the research staff from consenting. 3 of the 10 RNAs stated that the player was dysfunctional, though the players were tested prior to delivery to the pre-operative area. 7 of the 12 patients stated that they ‘forgot’ to listen to the CD prior to surgery, or that the nurses did not let them take the time to listen. Only 2 of the 12 patients actually listened to the CD prior to surgery; only 2 of the 12 had the CD played during surgery. 4 of the 12 never received the CD player and surveys after surgery on the surgical oncology floor. Only 1 of the 12 actually listened to the CD throughout the entire hospital stay. 5 patients were told that it was “too busy” to listen to the CD by the floor nursing staff. 6 CD players were lost or stolen during the course of the study. To date, only 1 patient in the control group completed all surveys. However, 3 patients voiced excitement and satisfaction when using the intervention CD during their immediate peri-operative time, and were documented by external observers to have resolution of their anxiety while using the intervention CD. Conclusions: While subjectively beneficial for patients to decrease stress responses peri-operatively, integrative medicine techniques such as guided imagery will be difficult to implement until the culture of medicine embraces this novel modality. Citation Format: Elizabeth L. Dickson, Matt Gerber, Amy L. Jonson. Guided imagery use in the peri-operative period of gynecologic oncology surgery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2013-1377