Patricia L. Judson

Trends in the incidence of invasive and in situ vulvar carcinoma.

OBJECTIVE: To characterize the incidence of vulvar carcinoma in situ and vulvar cancer over time. METHODS: We used the Surveillance Epidemiology and End Results database to assess trends in the incidence of vulvar cancer over a 28-year period (1973 through 2000) and determined whether there had been a change in incidence over time. Information collected included patient characteristics, primary tumor site, tumor grade, and follow-up for vital status. We calculated the incidence rates by decade of age, used χ2 tests to compare demographic characteristics, and tested for trends in incidence over time. RESULTS: A total of 13,176 in situ and invasive vulvar carcinomas were identified; 57% of the women were diagnosed with in situ, 44% with invasive disease. Vulvar carcinoma in situ increased 411% from 1973 to 2000. Invasive vulvar cancer increased 20% during the same period. The incidence rates for in situ and invasive vulvar carcinomas are distributed differently across the age groups. In situ carcinoma incidence increases until the age of 40–49 years and then decreases, whereas invasive vulvar cancer risk increases as a woman ages, increasing more quickly after 50 years of age. CONCLUSION: The incidence of in situ vulvar carcinoma is increasing. The incidence of invasive vulvar cancer is also increasing but at a much lower rate. LEVEL OF EVIDENCE: III

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.

Lymphatic Mapping and Sentinel Lymph Node Biopsy in Women With Squamous Cell Carcinoma of the Vulva: A Gynecologic Oncology Group Study

PURPOSE To determine the safety of sentinel lymph node biopsy as a replacement for inguinal femoral lymphadenectomy in selected women with vulvar cancer. PATIENTS AND METHODS Eligible women had squamous cell carcinoma, at least 1-mm invasion, and tumor size ≥ 2 cm and ≤ 6 cm. The primary tumor was limited to the vulva, and there were no groin lymph nodes that were clinically suggestive of cancer. All women underwent intraoperative lymphatic mapping, sentinel lymph node biopsy, and inguinal femoral lymphadenectomy. Histologic ultra staging of the sentinel lymph node was prescribed. RESULTS In all, 452 women underwent the planned procedures, and 418 had at least one sentinel lymph node identified. There were 132 node-positive women, including 11 (8.3%) with false-negative nodes. Twenty-three percent of the true-positive patients were detected by immunohistochemical analysis of the sentinel lymph node. The sensitivity was 91.7% (90% lower confidence bound, 86.7%) and the false-negative predictive value (1-negative predictive value) was 3.7% (90% upper confidence bound, 6.1%). In women with tumor less than 4 cm, the false-negative predictive value was 2.0% (90% upper confidence bound, 4.5%). CONCLUSION Sentinel lymph node biopsy is a reasonable alternative to inguinal femoral lymphadenectomy in selected women with squamous cell carcinoma of the vulva.

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.

On the apparent failure of adjuvant pelvic radiotherapy to improve survival for women with uterine sarcomas confined to the uterus.

Despite numerous studies documenting reduction of pelvic relapses after adjuvant pelvic radiotherapy stage I and II uterine sarcomas, improved survival remains unproven. This retrospective report analyzes patterns of failure, survival, and toxicity in 42 women with stage I and 7 patients with stage II uterine sarcomas treated from 1972 through 1998 to identify patients likely to benefit from pelvic or abdominal radiotherapy and chemotherapy. Four of these patients also received adjuvant chemotherapy. There were 20 leiomyosarcomas, 18 homologous mixed mullerian tumors, and 11 heterologous mixed mullerian tumors. Disease-free survivals for mixed mullerian tumors were 65% at 5 years and 61% at 15 years. Disease-free survivals for leiomyosarcomas were 40% at 5 years and 40% at 15 years. There were 14 distant only, 5 distant and abdominal, 1 abdominal, 1 distant and pelvic, and 2 unknown initial sites of failure. Acute toxicity was acceptable as measured by a median 1-kg weight loss from radiotherapy and a 2% rate of failure to complete therapy. Chronic toxicity consisted of 3 small bowel obstructions and 1 sigmoid colon obstruction. In conclusion, the efficacy of adjuvant pelvic radiation is demonstrated by the absence of any isolated pelvic failures. Although the frequent occurrence of peritoneal failures suggests a role for prophylactic abdominal radiation for mixed mullerian tumors, more effective systemic therapy is necessary to substantially increase the chance of cure for women with early-stage uterine sarcomas.

Hysteroscopy and cytology in endometrial cancer.

OBJECTIVE: To estimate the effect of preoperative diagnostic hysteroscopy on peritoneal cytology in patients with endometrial cancer. METHODS: A total of 256 charts were reviewed. Two cohorts were established based on diagnosis by hysteroscopy or blind endometrial sampling via either endometrial biopsy or dilatation and curettage (D&C). Malignant or suspicious peritoneal cytology was the primary outcome. Cohorts were compared using logistic regression to correct for potential confounders of stage and grade. RESULTS: A total of 204 cases were diagnosed by endometrial biopsy or D&C, whereas 52 were identified by hysteroscopy. In the endometrial biopsy or D&C arm, 14 of 204 (6.9%) patients had malignant or suspicious cytology compared with 7 of 52 (13.5%) patients in the hysteroscopy arm (P = .15). After logistic regression controlling for stage and grade, the odds ratio for positive cytology after hysteroscopy was 3.88 (95% confidence interval 1.11,13.6; P = .03). Four of the 52 (7.7%) cases diagnosed by hysteroscopy were stage IIIA due to cytology alone compared with 3 of the 204 (1.4%) cases diagnosed by endometrial biopsy or D&C (P = .03). CONCLUSION: Hysteroscopy appears to be associated with an increased rate of malignant cytology after controlling for confounders of stage and grade. Further, there appears to be an association between hysteroscopy and upstaging patients due to cytology alone. LEVEL OF EVIDENCE: II-2

Vulvar cancer in young women: demographic features and outcome evaluation.

OBJECTIVE The objective of the study was to identify prognostic and environmental factors associated with vulvar carcinoma in young women. STUDY DESIGN This study was a review of patients younger than 45 years who were diagnosed with vulvar squamous cell carcinoma between 1994 and 2006. RESULTS Fifty-six patients were identified. Median age was 38 years and median follow-up was 25.3 months. Fifty-eight percent of patients presented with stage I disease; 77% smoked tobacco. Of patients with advanced disease, 53.3% were smokers, 40% had human papillomavirus (HPV) exposure, 46.7% had a history of vulvar intraepithelial neoplasia (VIN), and 6.7% were immunocompromised. Symptoms were present for more than 12 months in 47%, but symptom duration did not correlate with stage (P = .42) or positive lymph nodes (P = .28). Disease recurred in 10.7% and 5.4% died of disease. CONCLUSION Young women with vulvar cancer tend to have early-stage disease, smoke, have a history of HPV, and have VIN. Many of the factors that place these patients at continuous risk are modifiable.

A prospective randomized trial of thalidomide with topotecan compared with topotecan alone in women with recurrent epithelial ovarian carcinoma

Thalidomide is an antiangiogenic agent with immune modulating potential. The objective of this study was to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide.

A phase II trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy.

OBJECTIVES The efficacy and safety of bevacizumab and docetaxel were evaluated in women who developed recurrent epithelial ovarian, fallopian, or peritoneal cancer within 12 months of platinum-based therapy. METHODS Patients received docetaxel (40 mg/m(2)) on days 1 and 8 and bevacizumab (15 mg/kg) on day 1 of a 21-daycycle. Primary endpoint was 6-month progression-free survival (PFS). RESULTS Forty-one patients were evaluable for PFS and 38 for best response; 46% had platinum-free intervals (PFI) of <6 months and 54% between 6 and 12 months. The 6-month PFS was 43.9% (95% confidence interval (CI(95%))=28.6-58.2%). Median PFS (months) was 5.2 (CI(95%)=4.4-7.2) for all patients, 6.2 (CI(95%)=4.1-7.4) for patients with PFI <6 months, and 5.1 (CI(95%)=3.0-7.2) for those with PFI ≥ 6 months. Twenty-two patients showed overall response (CR+PR) (57.9%; CI(95%)=40.8-73.7%), and 32 showed clinical benefit (CR+PR+SD) (84.2%; CI(95%)=68.8-94.0%). For those with complete or partial responses, median duration of response was 4.8 months (0.7-14.5). Median overall survival was 12.4 months (CI(95%)=10.0-21.9). The most common grade 3/4 adverse events (AEs) were neutropenia (14.6% of patients), followed by leukopenia, fatigue, metabolic, and gastrointestinal, with 66% showing any grade 3/4 toxicity. Most common AEs of any grade were gastrointestinal (93%), fatigue (73%), and pain (73%). Four (10%) patients developed hypertension, 1 a gastrointestinal perforation, and another a colovesicular fistula. CONCLUSIONS Bevacizumab and docetaxel administered in patients with recurrent ovarian cancer is an active regimen without new unanticipated toxicities. This combination should be an option for further study or clinical use in recurrent ovarian cancer.

A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth.

Elevated serum levels of hepatocyte growth factor (HGF) and high tumor expression of c-Met are both indicators of poor overall survival from ovarian cancer (OVCA). In the present study, we evaluated the role of the HGF signaling pathway in OVCA cell line chemoresistance and OVCA patient overall survival as well as the influence of HGF/c-Met signaling inhibition on the sensitivity of OVCA cells to combinational carboplatin plus paclitaxel therapy. The prevalence of the HGF receptor, c-Met, was determined by immunohistochemistry in primary OVCA samples (n=79) and OVCA cell lines (n=41). The influence of the c-Met-specific inhibitor MK8033 on OVCA cell sensitivity to combinations of carboplatin plus paclitaxel was examined in a subset of OVCA cells (n=8) by CellTiter-Blue cell viability assays. Correlation tests were used to identify genes associated with response to MK8033 and carboplatin plus paclitaxel. Identified genes were evaluated for influence on overall survival from OVCA using principal component analysis (PCA) modeling in an independent clinical OVCA dataset (n=218). Immunohistochemistry analysis indicated that 83% of OVCA cells and 92% of primary OVCA expressed the HGF receptor, c-Met. MK8033 exhibited significant anti-proliferative effects against a panel of human OVCA cell lines. Combination index values determined by the Chou-Talalay isobologram equation indicated synergistic activity in combinations of MK8033 and carboplatin plus paclitaxel. Pearsons correlation identified a 47-gene signature to be associated with MK8033-carboplatin plus paclitaxel response. PCA modeling indicated an association of this 47-gene response signature with overall survival from OVCA (P=0.013). These data indicate that HGF/c-Met pathway signaling may influence OVCA chemosensitivity and overall patient survival. Furthermore, HGF/c-Met inhibition by MK8033 represents a promising new therapeutic avenue to increase OVCA sensitivity to carboplatin plus paclitaxel.