Charles A. Leath

Randomized, Double-Blind, Placebo-Controlled Phase II Study of AMG 386 Combined With Weekly Paclitaxel in Patients With Recurrent Ovarian Cancer

PURPOSE To estimate the efficacy and toxicity of AMG 386, an investigational peptide-Fc fusion protein that neutralizes the interaction between the Tie2 receptor and angiopoietin-1/2, plus weekly paclitaxel in patients with recurrent ovarian cancer. PATIENTS AND METHODS Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned 1:1:1 to receive paclitaxel (80 mg/m(2) once weekly [QW], 3 weeks on/1 week off) plus intravenous AMG 386 10 mg/kg QW (arm A), AMG 386 3 mg/kg QW (arm B), or placebo QW (arm C). The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response, CA-125 response, safety, and pharmacokinetics. RESULTS One hundred sixty-one patients were randomly assigned. Median PFS was 7.2 months (95% CI, 5.3 to 8.1 months) in arm A, 5.7 months (95% CI, 4.6 to 8.0 months) in arm B, and 4.6 months (95% CI, 1.9 to 6.7 months) in arm C. The hazard ratio for arms A and B combined versus arm C was 0.76 (95% CI, 0.52 to 1.12; P = .165). Further analyses suggested an exploratory dose-response effect for PFS across arms (Tarones test, P = .037). Objective response rates for arms A, B, and C were 37%, 19%, and 27%, respectively. The incidence of grade ≥ 3 adverse events (AEs) in arms A, B, and C was 65%, 55%, and 64%, respectively. Frequent AEs included hypertension (8%, 6%, and 5% in arms A, B, and C, respectively), peripheral edema (71%, 51%, and 22% in arms A, B, and C, respectively), and hypokalemia (21%, 15%, and 5% in arms A, B, and C, respectively). AMG 386 exhibited linear pharmacokinetic properties at the tested doses. CONCLUSION AMG 386 combined with weekly paclitaxel was tolerable, with a manageable and distinct toxicity profile. The data suggest evidence of antitumor activity and a dose-response effect, warranting further studies in ovarian cancer.

Transcriptional targeting of tumors with a novel tumor-specific survivin promoter

It has been demonstrated that survivin, a novel member of the inhibitor of apoptosis (IAP) protein family, is expressed in human cancers but is undetectable in normal differentiated tissues. We employed a recombinant adenoviral vector (reAdGL3BSurvivin) in which a tumor-specific survivin promoter and a luciferase reporter gene were inserted into the E1-deleted region of adenovirus vector. Luciferase activity was measured in both multiple tumor cell lines and two primary melanoma cells infected with reAdGL3BSurvivin. Human fibroblast and mammary epithelial cell lines were used as negative controls. A reAdGL3CMV, containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity generated by the survivin promoter. Our data revealed that the survivin promoter showed high activity in both established tumor cell lines and the primary melanoma cells. In contrast, the in vivo studies indicated that the activities of survivin promoter were extremely low in the major mouse organs. The survivin promoter appears to be a promising tumor-specific promoter exhibiting a “tumor on” and “liver off” profile, and therefore, it may prove to be a good candidate for transcriptional targeting of cancer gene therapy in a wide variety of tumors.

Validation of referral guidelines for women with pelvic masses.

OBJECTIVE: Guidelines for referring women with pelvic masses suspicious for ovarian cancers to gynecologic oncologists have been published jointly by Society of Gynecologic Oncologists (SGO) and the American College of Obstetricians and Gynecologists (ACOG). They are based on patient age, CA 125 level, physical findings, imaging study results, and family history. Although the guidelines are evidence-based, their predictive value in distinguishing cancers from benign masses is unknown. METHODS: Chart review for factors included in the guidelines of surgically evaluated women with pelvic masses at 7 tertiary care centers during a 12-month interval was performed. This information was used to estimate the predictive values of the SGO and ACOG guidelines in identifying patients with malignant pelvic masses. RESULTS: A total of 1,035 patients were identified, including 318 (30.7%) with primary malignancies of the ovary, fallopian tube, or peritoneum. Seventy-seven were younger than 50 years old (premenopausal group), and 240 were 50 years old or older (postmenopausal group). Fifty additional patients (4.8%) had cancers metastatic to the ovaries, and the remaining 667 (64.4%) had benign masses. The referral guidelines captured 70% of the ovarian cancers in the premenopausal group and 94% of the ovarian cancers in the postmenopausal group. The positive predictive value was 33.8% for the premenopausal group and 59.5% for the postmenopausal group, whereas the negative predictive values were more than 90% for both groups. Elevated CA 125 level was the single best predictor of malignancy in both groups. CONCLUSION: The SGO and ACOG referral guidelines effectively separate women with pelvic masses into 2 risk categories for malignancy. This distinction permits a rational approach for referring high-risk patients to a gynecologic oncologist for management. LEVEL OF EVIDENCE: III

Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter

Adenoviral vectors are considered to be good gene delivery vectors for cancer gene therapy due to their wide host tissue range and cell cycle-independent infectivity. However, the disadvantages include the lack of specificity for cancer cells and the high liver accumulation in vivo. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. We explored the CXCR4 promoter as a candidate to restrict adenoviral transgene expression to tumor cells with a low expression in host tissues. The luciferase activities in multiple cancer cell lines infected with recombinant adenovirus reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter exhibited relatively high transcriptional activity in a breast cancer cell line, MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65% (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both normal cell lines HFBC and HMEC. In addition, CXCR4 had a low expression of luciferase (0.32%) compared to that of the CMV promoter in mouse liver in vivo. The data also revealed that the CXCR4 promoter was a stronger tumor-specific promoter (TSP) than the Cox-2M promoter in primary melanomas obtained from two patients. The CXCR4 promoter is shown to have a ‘tumor-on’ and ‘liver-off’ status in vitro and in vivo, and CXCR4 may prove to be a good candidate TSP for cancer gene therapy approaches for melanoma and breast cancers.

Chemotherapy for advanced and recurrent cervical carcinoma: Results from cooperative group trials

OBJECTIVE To review the clinical trial experience with chemotherapy for patients with primary Stage IVB, persistent and recurrent cervical cancer. METHODS PubMed and cooperative group website search was performed and included clinical trials until September 2012. Emphasis was placed on the phase II and III clinical trial experience of the Gynecologic Oncology Group. RESULTS Experience and trial results with single agents and combination agents in phase II settings are reviewed. Cisplatin has been considered as the most effective agent for metastatic cervical cancer. Most patients who develop metastatic disease have received cisplatin with concurrent radiation and may no longer be sensitive to single-agent therapy. Therefore, cisplatin-based combination chemotherapy regimens have been extensively studied and eight sentinel phase III trials are discussed in this review. CONCLUSION Based on phase III results, the combination of cisplatin and paclitaxel remains the standard of care; however, alternative combination therapies including cisplatin/topotecan and cisplatin/gemcitabine may be acceptable considerations for patients when considering potential toxicities. Further research is necessary to determine the optimal therapy for this group of patients. Final data from GOG 240 and JCOG 0505 will likely contribute to the design of future clinical trials in this disease setting.

Preclinical evaluation of a class of infectivity-enhanced adenoviral vectors in ovarian cancer gene therapy

Ovarian carcinoma cells are often infected inefficiently by adenoviruses (Ad) due to low expression of coxsackie–adenovirus receptors (CAR), hindering the application of adenovirus-mediated gene therapy in ovarian cancer. In this study, we explored a class of infectivity-enhanced Ad vectors, which contain CAR-independent targeting motifs RGD (Ad5.RGD), polylysine (Ad5.pK7), or both (Ad5.RGD.pK7), for their utility in ovarian cancer gene therapy using in vitro and in vivo model systems. We found that these vectors infected established ovarian carcinoma cell lines and primary ovarian cancer cells with significantly enhanced infectivity. Among them, Ad5.RGD.pK7 appeared to be most efficient. Further, we evaluated their gene delivery efficiency using two different ovarian cancer mouse models – subcutaneous and intraperitoneal human ovarian cancer xenografts. All of the modified vectors appeared to be more efficient than the unmodified Ad5 vector in both models, although some of the differences are not statistically significant. Of these, Ad5.RGD.pK7 exhibited the highest efficacy in the subcutaneous tumor model, while Ad5.pK7 worked most efficiently in the intraperitoneal tumor model. These preclinical results suggest that Ad5.RGD.pK7 and Ad5.pK7 may be very useful in ovarian cancer gene therapy.

Surgical staging in endometrial cancer.

Early presentation of endometrial cancer permits effective management with excellent clinical outcome. The addition of hysteroscopy to dilatation and curettage (D&C) in the evaluation of postmenopausal bleeding adds little to the detection of malignancy. Imaging studies such as computed tomography, magnetic resonance imaging, and positron-emission tomography may be of use in determining the presence of extrauterine disease in patients medically unfit for surgical staging. However, these studies are not sufficiently sensitive to replace surgical staging and have little role in routine preoperative evaluation. Clinical staging alone is clearly inadequate, as 23% of preoperative clinical stage I/II patients are upstaged with comprehensive surgical staging. Preoperative tumor grade from D&C or office biopsy may be inaccurate and lead to an underestimate of tumor progression if used to determine which patients should be surgically staged. Clinical estimation of depth of invasion, with or without frozen section, is inaccurate and may lead to underestimation of disease status when surgical staging is not performed. The practice of resecting only clinically suspicious nodes should be discouraged as it is no substitute for comprehensive surgical staging. Comprehensive surgical staging provides proper guidance for postoperative adjuvant therapy, avoiding needless radiation in 85% of clinical stage I/II patients. Finally, resection of occult metastasis with surgical staging may improve survival.

Hospice enrollment for terminally ill patients with gynecologic malignancies: Impact on outcomes and interventions

OBJECTIVE To determine survival and interventions for patients with non-curative gynecologic malignancies based on supportive care enrollment. METHODS An IRB approved retrospective review identified patients with recurrent/persistent gynecologic cancers from 2002 to 2008. Demographics, therapy, clinicopathologic data, hospice utilization, surgical/invasive procedures and survival were collected. Patients were considered hospice enrollees if they enrolled following recommendation from their provider (HOSPICE); however, patients that declined hospice when recommended were considered (NO HOSPICE), regardless if they ultimately received supportive care. Standard statistical tests including: t-test and Kaplan-Meier with Log Rank were used. RESULTS Eighty-one patients were identified: 29 patients (36%) NO HOSPICE and 52 (64%) HOSPICE. Mean age was 61. Most patients had ovarian cancer (54.3%), were white (61.7%) and had disease recurrence (72%). Patients utilized a median of 3 anti-neoplastic therapies (range 0-10) for recurrent or progressive/persistent disease. Median time receiving hospice care was 1week for NO HOSPICE patients versus 8weeks HOSPICE patients (p<0.0005). In a subset of patients with recurrent disease, median overall survival for NO HOSPICE patients was 9months (95% CI 5.9-12.1months) versus 17months (95% CI 11.1-22.9months) for HOSPICE patients (p=0.002). NO HOSPICE patients were more likely to have a procedure performed (55% vs. 31%) within 4weeks of their death, including the administration of chemotherapy OR 2.4 (95% CI 1.1-7.1, p=0.036). CONCLUSIONS While retrospective reviews evaluating hospice are challenging, our data suggest no detrimental impact on survival for hospice patients. Continued evaluation for patients at the end-of-life is necessary in order to optimize resource utilization.

KNOWLEDGE, BELIEFS, AND PRACTICES CONCERNING SEAT BELT USE DURING PREGNANCY

OBJECTIVE This study seeks to evaluate the comprehension of and attitudes toward proper restraint use among women attending prenatal care clinics. METHODS Four-hundred and fifty women were asked to complete a survey during prenatal care visits at county health department clinics; the response rate was 92.0%. Women were asked to provide demographic information and report their frequency and knowledge of proper automobile restraint use. RESULTS Nearly all subjects (95.4%) either maintained or increased their pre-pregnancy frequency of restraint use. Three-hundred (72.5%) subjects demonstrated that they wore their restraints in the correct location, with women who wore restraints more frequently being more likely to report correct placement. Two-hundred and forty-nine (60.1%) of women reported that restraints would protect their baby if they were involved in a collision, while 48 (11.6%) thought the restraints would cause injury to their baby, and 153 (37.0%) were unsure. Women who reported that restraints would protect them and their baby if involved in a collision were significantly more likely to report always wearing restraints compared with those who were unsure or had negative perceptions of restraints (84.4% vs. 64.6%; p < 0.0001). The most commonly reported reasons for lack of restraint use were lack of comfort (52.8%) and forgetfulness (42.5%). Only 36.9% percent of women reported receiving information regarding restraint use during their current pregnancy. CONCLUSIONS Many gravid women lack information regarding proper seat belt use and their role in injury prevention. Consequently, the frequency of seat belt use and its correct placement are negatively impacted. Health care workers should take an active role in educating pregnant gravid women about proper restraint use.

Uterine leiomyosarcoma metastatic to the thyroid

BACKGROUND Uterine leiomyosarcoma is an aggressive tumor that has a propensity for distant metastasis. Distant sites of spread include the lung, liver, brain, and bone. CASE A woman in her 5th decade was diagnosed with stage IV leiomyosarcoma of the uterus. Distant metastasis in the chest was confirmed by thoracotomy at the time of her original diagnosis. She subsequently experienced multiple episodes of metastasis including metastatic disease to her thyroid. She survived 71 months after diagnosis of stage IV disease. CONCLUSION Our case represents the first reported experience with uterine leiomyosarcoma metastatic to the thyroid. Additionally the case is notable because the patient experienced multiple episodes of asymptomatic stable disease after repetitive chemotherapeutic regimens.