Natalie S. Gould

Impact of individual physicians on enrollment of patients into clinical trials.

&NA; The National Cancer Institute is committed to increasing enrollment of cancer patients in clinical treatment trials. The factors that achieve successful results are poorly understood. This study analyzes the role of individual physicians in recruitment of patients in clinical trials. A retrospective review was undertaken of all patients with untreated endometrial, cervical, or ovarian cancer potentially eligible for a multi‐institutional phase III trial cared for by the Section of Gynecologic Oncology at the University of Oklahoma from July 1, 1998 to September 30, 1999. Patient variables assessed included age, insurance status, cancer diagnosis, and enrollment onto clinical trial. There was no difference in faculty patients with regard to cancer type, age, or insurance status. There was a significant difference (p < 0.01) between faculty in offering protocol therapy and likelihood of successfully enrolling patients. Successful enrollment was correlated with faculty experience and principal investigator status. This study shows that availability of patients, patient variances, support staff, and institutional commitment are secondary to individual physician factors in determining successful enrollment of patients onto clinical trials.

Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists

The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute’s human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARγ-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.

Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: A gynecologic oncology group study

PURPOSE Intraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle. METHODS Patients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135mg/m(2) IV over 3h followed by cisplatin 75mg/m(2) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3-5 non-hematologic toxicity occurring within the first 4 cycles of treatment. RESULTS Twenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain. CONCLUSIONS This modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172.

Impact of histology and surgical approach on survival among women with early-stage, high-grade uterine cancer: An NRG Oncology/Gynecologic Oncology Group ancillary analysis

OBJECTIVES We sought to analyze the clinicopathologic features, recurrence patterns and survival outcomes of women with high-grade uterine cancer (UC) enrolled on The Gynecologic Oncology Group (GOG) LAP2 trial. METHODS This is a post-hoc analysis of LAP-2 patients with grade 3 endometrioid adenocarcinoma (ENDO), uterine serous (USC), clear cell (CC) and carcinosarcoma (CS). Demographics, clinicopathologic features, and recurrence patterns, were compared by histology and surgical approach. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS Of the 2600 patients enrolled in LAP-2, 753 patients had high-grade UC: 350 had ENDO, 289 had USC, 42 had CC and 72 had CS. Compared with the ENDO cohort, those with other high-grade subtypes were older (p<0.001) and were more likely to have positive peritoneal cytology (p<0.001), positive lymph nodes (p=0.05) and higher disease stage on final pathology (p<0.001). With a median follow-up time of 60months, compared to patients with ENDO, those with USC, CCC and CS subtypes had higher recurrence rates (p<0.001), extra-pelvic recurrences (p<0.001) and poorer PFS (p<0.001) and OS (p<0.001). Those diagnosed with USC and CS experienced the worst survival outcomes (p=0.003). Patterns of recurrence and survival were not different in those staged with LSC vs LAP. On multivariable analysis, age, stage, pelvic washings and Type II histology were independently and adversely associated with survival. CONCLUSIONS Women with apparent early-stage, USC and CS histologies have poorer outcomes than women with grade 3 endometrioid adenocarcinoma. Patterns of recurrence and survival were not impacted by surgical approach.

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II-IV ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60 mg/m(2) on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment. RESULTS Patients were treated with paclitaxel 175 mg/m(2) IV and carboplatin IP from AUC 5-7 on day 1 and paclitaxel 60 mg/m(2) IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4 cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2 week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135 mg/m(2) IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4 cycles with one DLT (grade 3 hyponatremia). CONCLUSIONS Paclitaxel at 175 mg/m(2) IV, carboplatin AUC 6 IP day 1 and paclitaxel 60 mg/m(2) IP day 8 yield 18-56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.

A phase i study with an expanded cohort to assess feasibility of intravenous docetaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with previously untreated ovarian, fallopian tube or primary peritoneal carcinoma

OBJECTIVE To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) docetaxel, intraperitoneal (IP) carboplatin and IP paclitaxel in women with stage II-IV untreated ovarian, fallopian tube or primary peritoneal carcinoma. METHODS Patients received docetaxel (55-75 mg/m(2)) IV and carboplatin (AUC 5-7) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8. A standard 3+3 design was used in the dose escalation phase. A 2-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. RESULTS The MTD determined during the dose escalation phase was day 1 docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP and day 8 IP paclitaxel 60 mg/m(2). Forty-six patients were enrolled in the feasibility portion at this dose level. Six were unevaluable. Fifteen evaluable patients had dose-limiting toxicities (DLTs) within the first four cycles. These DLTs were prolonged neutropenia (2), neutropenic fever (7), grade 4 thrombocytopenia (1), grade 4 dehydration (1), grade 3 infection (2), grade 3 oral mucositis (1) and pulmonary embolism (1). CONCLUSIONS Docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP administered on day 1, and paclitaxel 60 mg/m(2) IP administered on day 8, is the MTD when considering one cycle of treatment but was not feasible over four cycles due to bone marrow toxicity. We recommend reduction of carboplatin to AUC 5 should this regimen be considered for treatment in women with newly diagnosed advanced ovarian cancer.

Malignancies arising in endometriosis

Abstract Malignant transformation of endometriosis is a well-documented process with over 300 cases presented in the literature. The majority of these cases arise in ovarian endometriosis; however, approximately 25% are found in extragonadal sites. Although not definitely proven, a theory has been proposed in several reports that the use of unopposed estrogen in women with a history of endometriosis who have undergone hysterectomy may be a contributing factor. Several of these studies have therefore suggested the addition of a progestational agent for these women. Endometriotic implants share not only a common histology with the endometrium, but also similar function and responsiveness to the hormonal milieu. As in the case of women with a uterus, and consequently an endometrium, the use of unopposed estrogen may present a risk factor for malignant transformation of endometriosis. Diagnosis and treatment of these malignancies is based on tumor location and histology, similar to analogous malignancies of the uterus and ovaries.

Adenoca of the uterus with cervical extension and adenoca of the cervix: are the clinical presentations truly different?

Abstract Objective: To identify the preoperative differences between patients with stage 2 endometrial cancer and with adenoca of the cervix. Methods: Seventy-four records were reviewed, and the following data were abstracted: abnormal Pap smear (APAP); abnormal bleeding, dysfunctional and postmenopausal (VAGBLD); postcoital bleeding (PCB); pelvic pain (PAIN); and dyspareunia (DYSP). Student t , χ 2 , and Cox proportional hazard tests were utilized. Results: There were 40 cervical cancers (54%) and 34 endometrial cancers (46%). Preoperatively, 23 patients (31%) had questionable cancer origin. Patients with cervical cancer were younger (50 versus 58, P = 0.05) and weighed less (162 versus 185, P = 0.08). Patients with cervical adenoca were more likely to present with APAP ( P = 0.02; RR 3.7, CI: 1.2–11.5), PCB ( P = 0.03; RR 8.0, CI: 1.1–7.1), and a smoking history ( P = 0.04; RR 2.9, CI: 1.0–8.5). Patients with uterine cancer had pelvic pain ( P = 0.04; RR 3.4, CI: 1.0–11.6). There were no significant differences in incidences of VAGBLD, DYSP, gravidity, or age at menarche. Predictors for cervical cancer APAP, PCB, age, and smoking remained significant upon multivariate analysis, as did the predictors PAIN ( P = 0.007) and age ( P = 0.05) for uterine cancer. Conclusion: Patients with cervical cancer were more likely to be younger, weigh less, and present with APAP and PCB, whereas uterine cancer patients were more apt to present with pelvic pain.

Hormone replacement practice patterns among Oklahoma physicians

Abstract Objective: To determine hormone replacement (HRT) patterns among ob-gyns (OBs), family practitioners (FPs), and internists (IMs). Methods: Anonymous written surveys were sent to OBs, FPs, and IMs within the state of Oklahoma. Practice patterns were compared using X 2 tests. A P value of 0.05 was considered significant. Results: Five hundred twenty-five of 1,341 surveys were returned, and 42.1% of OBs, 25.2% of FPs, and 16.3% of IMs stated that they prescribe HRT to 90% of their postmenopausal patients (OBs versus FPs P = 9×10 -4 ; OBs versus IMs P = 1×10 -6 ). Urban physicians prescribed HRT to > 90% of their postmenopausal patients (urban 38.8%, rural 19.9%, P = 5×10 -4 ). A trend towards increased HRT prescribing was seen for physicians in practice 5 years or less compared with those in practice longer ( P = 0.06). Multiple logistics regression found specialty ( P = 0.02), urban practice ( P = 0.01), and years in practice ( P = 0.05) as independent predictors for prescribing HRT to 91–100% of postmenopausal patients. Unopposed estrogen was the favored HRT for all specialties in postmenopausal women with prior hysterectomies. Women with a history of endometriosis who received a hysterectomy were more likely to receive unopposed estrogen for HRT if they were postmenopausal (77.6%) than if they were premenopausal (68.4%). Finally, differences were seen between specialties in requiring a mammogram before starting HRT (OBs 66.9%; FPs 84.7%; IMs 91.7%; OBs versus FPs P = 1×10 -4 ; OBs versus IMs P = 3×10 -7 ; FPs versus IMs ( P = 0.05). Conclusions: Significant differences exist between the practice patterns of OBs, FPs, and IMs. This indicates a need for OBs to promote the benefits of HRT to physicians who are not ob-gyns.