Consolidation strategies in ovarian cancer: observations for future clinical trials.

PURPOSE.: To describe the characteristics of a series of study populations of ovarian cancer patients with identical eligibility criteria in second or subsequent clinical remission (cCR) and to propose endpoint benchmarks for future consolidation studies. PATIENTS AND METHODS.: The patient populations consisted of those (1) untreated (U; observed until progression; n=35, (2) receiving imatinib (G; n=32), (3) receiving goserelin and bicalutamide (A; n=32), and (4) receiving vaccine (V; n=68; total=167). The endpoint of the combined analysis was progression-free survival in second remission (PFS 2). Patient characteristics were compared by chi-square test, and factors predicting PFS 2 evaluated in multivariate Cox model. RESULTS.: Groups were comparable for age, stage, grade, and debulking. Multivariate model to predict PFS 2 duration included histology, stage, optimal debulking, PFS 1 duration, and the type of intervention. As a benchmark for future studies, the median PFS 2 of the combined population of G, A, and U (removing V which had the most impact in prolonging PFS 2, n=68) was 11.3 months (95% CI: 10.4-12.5 months). The percent of patients with PFS 2>PFS 1 was 14/90 (16%). At 12 months, 43% remain progression-free. CONCLUSION.: Preliminary benchmarks for efficacy endpoints are suggested for future consolidation trials of patients in cCR. However, the suggested strategies will require validation in randomized trials and larger data sets.

Pilot study of a heptavalent vaccine-keyhole limpet hemocyanin conjugate plus QS21 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer.

PURPOSE: To characterize the safety and immunogenicity of a heptavalent antigen-keyhole limpet hemocyanin (KLH) plus QS21 vaccine construct in patients with epithelial ovarian, fallopian tube, or peritoneal cancer in second or greater complete clinical remission. EXPERIMENTAL DESIGN: Eleven patients in this pilot trial received a heptavalent vaccine s.c. containing GM2 (10 microg), Globo-H (10 microg), Lewis Y (10 microg), Tn(c) (3 microg), STn(c) (3 microg), TF(c) (3 microg), and Tn-MUC1 (3 microg) individually conjugated to KLH and mixed with adjuvant QS21(100 microg). Vaccinations were administered at weeks 1, 2, 3, 7, and 15. Periodic blood and urine samples were obtained to monitor safety (complete blood count, comprehensive panel, amylase, thyroid-stimulating hormone, and urinalysis) and antibody production (ELISA, fluorescence-activated cell sorting, and complement-dependent cytotoxicity). RESULTS: Eleven patients were included in the safety analysis; 9 of 11 patients remained on study for at least 2 weeks past fourth vaccination and were included in the immunologic analysis (two withdrew, disease progression). The vaccine was well tolerated. Self-limited and mild fatigue (maximum grade 2 in two patients), fever, myalgia, and localized injection site reactions were most frequent. No clinically relevant hematologic abnormalities were noted. No clinical or laboratory evidence of autoimmunity was seen. Serologic responses by ELISA were largely IgM against each antigen with the exception of Tn-MUC1 where both IgM and IgG responses were induced. Antibody responses were generally undetectable before immunization. After immunization, median IgM titers were as follows: Tn-MUC1, 1:640 (IgG 1:80); Tn, 1:160; TF, 1:640; Globo-H, 1:40; and STn, 1:80. Only one response was seen against Lewis Y; two were against GM2. Eight of nine patients developed responses against at least three antigens. Antibody titers peaked at weeks 4 to 8 in all patients. Fluorescence-activated cell sorting and complement-dependent cytotoxicity analysis showed substantially increased reactivity against MCF7 cells in seven of nine patients, with some increase seen in all patients. CONCLUSIONS: This heptavalent-KLH conjugate plus QS21 vaccine safely induced antibody responses against five of seven antigens. Investigation in an adequately powered efficacy trial is warranted.

Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus.

BACKGROUND: Endocervical adenocarcinomas of the usual type are etiologically related to infection with oncogenic human papillomaviruses (HPVs). These tumors are typically diffusely positive for p16 and carcinoembryonic antigen (CEA) immunostains. The goal of our study was to determine the HPV status and immunohistochemical profiles of unusual histologic subtypes of endocervical adenocarcinoma. METHODS: The study consisted of a total of 26 cases of unusual subtypes including clear cell carcinoma (CCC, n=9), gastric-type adenocarcinoma (GAS, n=11), minimal deviation adenocarcinoma (MDA, n=3), mesonephric adenocarcinoma (MSN, n=1), serous adenocarcinoma (SER, n=1), and malignant mixed Müllerian tumor (n=1). In addition, 5 cases of usual-type endocervical adenocarcinoma (UEA) were included in the study as a control group. The cases were tested for HPV using SPF-10 PCR and LiPA assays, and immunostained for p16, HIK1083, hepatocyte nuclear factor 1-ß, p53, CEA, estrogen receptor (ER), and progesterone receptor (PR). RESULTS: HPV DNA was not detected in any of the unusual adenocarcinoma subtypes, with the exception of a single case of SER in which HPV16 was detected. p16 positivity did not correlate with HPV status, as 42% of HPV-negative tumors showed patchy/diffuse p16 overexpression; however, p16 positivity was uncommon in GAS/MDA. HIK1083 positivity was limited to GAS and MDA, indicating relative specificity for tumors with gastric mucin expression. Hepatocyte nuclear factor 1-ß was positive in the majority of CCCs and also in other tumor variants and in some UEA as well, indicating a lack of specificity for clear cell differentiation. CEA was consistently negative in CCCs and in a single MSN, but positive in GAS, MDA, SER, and UEA, suggesting that it may serve as a negative marker of clear cell differentiation. p53 was diffusely positive in almost half of the GAS cases, whereas UEA showed mostly negative staining and other variants showed focal staining. PR was negative in all variant cases and in all UEA. ER expression, although mostly negative, showed focal staining in a few variant cases and UEA. CONCLUSIONS: Unusual variants of endocervical adenocarcinoma are not related to HPV infection, with only rare exceptions, and p16 overexpression in non-UEA does not correlate with HPV status. Negative staining for PR and ER may serve as a general marker of endocervical neoplasia. GAS/MDA may be differentiated from all other adenocarcinomas with either positive HIK1083 stain or negative/focal p16 stain. Positive CEA stain differentiates GAS/MDA from CCC and negative PR and ER stains differentiate GAS/MDA from benign endocervical glands. CCC may be distinguished from all other adenocarcinomas, except MSN, with a negative CEA stain. Strong and diffuse p53 positivity in SER may be useful in differentiation from UEA. MSN may be identified with negative CEA, ER, and PR stains.

Lymphoma in pregnancy initially diagnosed as vaginal intraepithelial neoplasia and lichen planus.

BACKGROUND: Non-Hodgkin's lymphoma presenting as a vaginal mass in pregnancy is uncommon. CASE: A 38-year-old primigravid woman presented at 27 weeks of gestation with vaginal lesions, bleeding, and discharge. Previous vaginal biopsies had been consistent with vaginal intraepithelial neoplasia 1 and lichen planus. After admission for this enlarging vaginal mass and bleeding, she was noted to have a newly palpable breast mass. Biopsy of the breast mass and subsequent re-evaluation of original vaginal biopsies were consistent with diffuse large B-cell lymphoma. She was treated with chemoimmunotherapy during pregnancy and delivered a viable neonate at term. CONCLUSION: Although benign vaginal conditions are common, non-Hodgkin's lymphoma should be considered in the differential diagnosis of persistent or enlarging vaginal lesions in pregnancy.

Stage-specific outcomes of patients with uterine leiomyosarcoma: a comparison of the international Federation of gynecology and obstetrics and american joint committee on cancer staging systems.

PURPOSE: Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation. RESULTS: Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices. CONCLUSION: Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.

A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission.

BACKGROUND: The current study was conducted to determine the effect of goserelin and bicalutamide on progression-free survival (PFS) in patients with epithelial ovarian cancer who were in second or greater complete disease remission. METHODS: Patients received bicalutamide at a dose of 50 mg orally daily and goserelin at a dose of 3.6 mg subcutaneously every 4 weeks. CA 125 was obtained monthly, with computed tomography performed every 3 months. Correlative studies included serum luteinizing hormone, follicle-stimulating hormone, vascular endothelial growth factor, free testosterone, and androstenedione and the germline polymorphisms CYP19A1 and androgen receptor. RESULTS: Between October of 2000 and October of 2002, 35 patients were enrolled. Three patients (9%) received therapy at the time of first disease remission and were removed from the study, and 1 patient (3%) was removed for liver function test abnormalities. The most frequent toxicities were grade 1 alkaline phosphatase (54%), fatigue (57%), and hot flashes (42%) based on the National Cancer Institute common toxicity scale, version 2.0. The PFS for patients receiving protocol therapy in second disease remission (21 patients) was 11.4 months (95% confidence interval [95% CI], 10.2-12.6 months). The PFS for patients receiving protocol therapy in third or fourth disease remission (11 patients) was 11.9 months (95% CI, 10.8-14.1 months). The percentage of patients remaining in second disease remission at given times are: 100% at 3 months, 100% at 6 months, 72% at 9 months, 47% at 12 months, 28% at 15 months, 22% at 18 months, 19% at 21 months, and 13% at 24 months. There were no associations noted between androgen receptor repeat number, genotype, allelotype, or haplotypes and PFS. CONCLUSIONS: The use of goserelin and bicalutamide did not appear to prolong PFS in patients with epithelial ovarian cancer in second or greater complete disease remission. The number of patients in disease remission at given time points may serve as a clinical trial endpoint for future studies of consolidation therapy.

CA125 level as a predictor of progression-free survival and overall survival in ovarian cancer patients with surgically defined disease status prior to the initiation of intraperitoneal consolidation therapy.

OBJECTIVES: Recent data suggest that differences in CA125 levels within the normal range may predict progression-free survival (PFS), but limited information is available regarding the value of these differences in predicting overall survival (OS) in patients with epithelial ovarian cancer. The objective of this study was to determine whether CA125 is an independent predictor of OS in patients with surgically defined disease status at the end of primary therapy prior to intraperitoneal (IP) consolidation chemotherapy. A secondary objective was to assess the relationship of CA125 level to PFS. METHODS: Using data from a retrospective cohort of 433 patients who received intraperitoneal (IP) therapy following primary treatment for ovarian cancer between 1984 and 1998, we identified 241 patients with a complete clinical response and CA125 data at the time of second-look surgery prior to IP chemotherapy. Patient demographics and updated follow-up status were abstracted from medical records. Kaplan-Meier survival curves were compared using the log-rank test, and Cox regression models were used for multivariate analysis. RESULTS: The majority of patients had advanced stage III or IV disease (n=201, 83%) and high-grade histology (n=163, 68%). Taxane was used as part of primary platinum-based therapy in 56% (n=134) of patients, and subsequent IP chemotherapy was platinum-based in 85% (n=206). When considered as a continuous variable, CA125 was a predictor of OS (P=0.029). Using the median CA125 level in our study group as a cut-off, OS was increased in patients with CA125 < or =12 U/ml (median 5.8 years) compared with >12 (3.7 years) (P=0.0027). CA125 level was an independent predictor of OS (HR: 1.410; 95% CI, 1.044, 1.904, P=0.0248) in a multivariate model that included stage (P=0.0166), grade (P=0.0001), and findings at second-look surgery (P=0.0003). CA125 level was also a predictor of clinical PFS (radiographic or CA125 elevation criteria alone) in a subset of 161 patients as a continuous variable (P=0.0036), and when divided at the median (< or = or >12; median 2.8 years vs. 1.7 years; P=0.0017). CONCLUSIONS: In our study population, CA125 level at the end of primary therapy was a predictor of OS and PFS when considered as a continuous variable, or when divided at the median (< or = or >12 U/ml). Further prospective study is required to optimize clinically significant cut-off values within the normal range of CA125 levels for both OS and PFS endpoints.

The impact of video-assisted thoracic surgery (VATS) in patients with suspected advanced ovarian malignancies and pleural effusions.

OBJECTIVES: We previously reported our initial experience of patients with suspected advanced ovarian cancer and moderate to large pleural effusions who underwent video-assessed thoracic surgery (VATS) before planned abdominal exploration. The objective of this study was to report the surgical findings and management of patients who underwent VATS in an update of our experience. METHODS: We performed a retrospective review of all patients with suspected advanced ovarian cancer and moderate to large pleural effusions who underwent VATS for assessment of extent of intrathoracic disease at our institution between 6/01 and 8/05. RESULTS: Twenty-three patients with a median age of 61 years (range, 36-79) were identified. VATS was performed for right-sided effusions in 17 patients (74%), and a median of 1350 ml (400-3700 ml) of pleural fluid was drained. VATS demonstrated macroscopic disease in 15 (65%) patients, with nodules >1 cm in 11/15 (73%), and nodules <1 cm in 4/15 (27%). Macroscopic intrathoracic disease was found in 4/10 (40%) patients with negative cytology. Intrathoracic cytoreduction was performed in 3/11 patients (27%) with intrathoracic disease >1 cm. After VATS, 12/23 patients (52%) underwent primary surgical management, with cytoreduction to < or =1 cm achieved in 11/12 patients (92%). The other eleven patients received primary chemotherapy after undergoing diagnostic laparoscopy alone (4/11) or no further abdominal exploration (7/11). Nine of these patients proceeded to interval cytoreduction, while 2 had pathology demonstrating upper gastrointestinal and lymphoma primaries at the time of VATS. Final diagnosis of primary site of disease included: ovary, 14 (61%); endometrial, 2 (9%); dual ovarian/endometrial primaries, 1 (4%); fallopian tube, 1 (4%); primary peritoneal, 1 (4%); other, 4 (17%). Overall, findings at VATS altered primary surgical management in 11/23 (48%) patients. CONCLUSIONS: Sixty-five percent of patients with suspected advanced ovarian cancer and moderate to large pleural effusions had gross intrathoracic disease identified at VATS, with the majority (11/15, 73%) having disease >1 cm in diameter. Use of VATS allows for assessment of intrathoracic disease and may help identify candidates for primary cytoreductive surgery and possible intrathoracic cytoreduction versus neoadjuvant chemotherapy.

Full-thickness diaphragmatic resection for stage IV ovarian carcinoma using the EndoGIA stapling device followed by diaphragmatic reconstruction using a Gore-tex graft: a case report and review of the literature.

BACKGROUND: Previous studies have reported the results of full-thickness diaphragmatic resection for ovarian cancer metastatic to the diaphragm. CASE: : We present the first case of an extensive full-thickness diaphragmatic resection performed using the EndoGIA [US Surgical Corp., Norwalk, CT] staple device followed by successful reconstruction using a Gore-tex (W.L. Gore and Associates, Inc., Newark, DE) graft. CONCLUSION: Full-thickness diaphragmatic resection using the EndoGIA stapling device is a safe and effective method to completely remove extensive tumor during cytoreductive surgery. Use of the stapler expeditiously assists in removal of the specimen with minimal blood loss. In cases where large defects cannot be repaired primarily, a Gore-tex patch should be used.

Laparoscopic findings during adnexal surgery in women with a history of nongynecologic malignancy.

OBJECTIVES: To describe the results of laparoscopic management of adnexal masses in women with a history of nongynecologic malignancy. METHODS: We conducted a retrospective review of 262 patients with history of prior nongynecologic malignancy who underwent laparoscopy for management of an adnexal mass between 1/1992 and 6/2004. RESULTS: Median patient age at laparoscopy was 55 years (range, 20-91 years), and median BMI was 25 kg/m2 (range, 14-41 kg/m2). Of the 262 patients, 145 (55.3%) had prior abdominal/pelvic surgery. Prior cancer history included breast (202, 77.1%), lymphoma/leukemia (16, 6.1%), colorectal (8, 3.0%), lung (7, 2.7%), multiple myeloma (5, 1.9%), head/neck (5, 1.9%), genitourinary (5, 1.9%), upper gastrointestinal (4, 1.5%), and other (10, 3.8%). Median ovarian mass diameter measured on radiologic imaging was 3.8 cm (range, 0.2-13.5 cm); median CA-125 was 17.0 U/mL (range, 1-7000 U/mL). In all, 49 (18.7%) patients had malignancy identified at laparoscopy, with 30/49 (61.2%) diagnosed with metastatic malignancy to the ovary and 19/49 (38.8%) having a new primary ovarian malignancy. Median tumor diameter and CA-125 were significantly higher in women found to have a malignancy (4.7 vs. 3.7 cm, and 35 vs. 14 U/mL, respectively). Overall, conversion to laparotomy occurred in 34 (12.9%) cases. Twenty-one of 49 (42.9%) patients with malignancy were converted to laparotomy compared with 13/213 (6.1%) when benign disease was noted (P < 0.001). CONCLUSIONS: Approximately 1 in 5 patients with a history of nongynecologic malignancy who were selected for laparoscopic management of an adnexal mass was found to have malignancy, with 60% being metastatic from other primaries. The majority of cases were managed laparoscopically even if malignancy was identified.

Update on surgical treatment for endometrial cancer.

In the USA, carcinoma of the endometrium consistently ranks as the most common malignancy of the female genital tract. Since the majority of cases present with abnormal clinical symptoms, these patients are typically identified at an early, curable stage when the neoplasm is still confined to the uterus. Surgical removal of the organ involved remains the cornerstone of treatment for this disease, and in light of this, surgery has replaced clinical examination as the staging modality of this malignancy. Surgery also appears to have a role in the management of advanced and recurrent disease. The surgical treatment of this disease is the focus of this review.

Embryo cryopreservation after diagnosis of stage IIB endometrial cancer and subsequent pregnancy in a gestational carrier.

OBJECTIVE: To describe a case of embryo cryopreservation before hysterectomy and bilateral salpingo-oophorectomy for endometrial cancer. DESIGN: Case report. SETTING: University and community service. PATIENT(S): An infertile woman with endometrial biopsy demonstrating grade II/III moderately differentiated endometrial adenocarcinoma. INTERVENTION(S): A Progestasert intrauterine device (IUD) was inserted into the uterine cavity to potentially reduce tumor proliferation during the stimulation cycle followed by oocyte retrieval and cryopreservation of 14 embryos. MAIN OUTCOME MEASURE(S): Pregnancy. RESULT(S): Successful pregnancy in a gestational carrier. CONCLUSION(S): Embryo cryopreservation and use of a gestational carrier may offer a fertility option for patients with endometrial malignancies without substantially delaying treatment.

Liposomal doxorubicin for treatment of metastatic chemorefractory vulvar adenocarcinoma.

BACKGROUND: Primaryadenocarcinoma of the vulva is a rare entity, and for widely metastatic vulvar adenocarcinoma, no effective treatment has been established. CASE: A 65-year-old woman was diagnosed with regionally advanced vulvar adenocarcinoma, with bulky involvement of bilateral groin lymph nodes, and associated extramammary Paget's disease. Initial therapy consisted of multiagent chemotherapy and vulvar and groin irradiation, followed by radical vulvectomy with groin and pelvic lymph node dissection. She subsequently developed widely metastatic disease including brain, pulmonary, hepatic, osseus, and subcutaneous lesions. Treatment with liposomal doxorubicin (Doxil) resulted in dramatic regression of metastatic lesions and marked improvement in quality-of-life. She remains clinically well, greater than 1 year since initiating Doxil treatment for widely metastatic vulvar adenocarcinoma, and has surpassed 5 years of survival since her initial diagnosis. CONCLUSIONS: We report the first case of Doxil used for the treatment of metastatic chemorefractory vulvar adenocarcinoma. We observed that Doxil was a well-tolerated and effective agent for this gynecologic malignancy, and warrants further investigation.

Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis.

OBJECTIVES: The objectives of this study were to (1) determine the incidence of lymph node micrometastasis in cervical cancer by immunohistochemical analysis and (2) determine if the presence of micrometastasis is a poor prognostic feature in early cervical cancer. METHODS: We retrospectively reviewed the medical records of 62 patients who underwent radical hysterectomy and lymphadenectomy for FIGO stage IA2-IB2 cervical cancer at Stanford University Hospital from 1990 to 2000. Forty-nine patients with negative lymph nodes were identified. A total of 976 formalin-fixed paraffin-embedded pelvic lymphadenectomy specimens were serially sectioned and stained with anti-cytokeratin antibodies AE1 and AE1/CAM5.2. RESULTS: Six patients had stage IA2 disease, 37 had stage IB1, and 6 had IB2. The mean age of the patients was 44 years (range, 24-76). Seventy-one percent had squamous cell carcinomas, 22% had adenocarcinomas, and 6% had other types. Lymph node micrometastases were immunohistochemically detected in 4 of the 49 (8.1%) patients, comprising 4 of 976 (0.41%) pelvic lymph nodes examined. Twelve of 45 (15.6%) patients with negative nodes had lymph-vascular space invasion (LVSI) whereas 3 of 4 (75%) patients with micrometastases had LVSI. At a mean follow-up time of 39.4 months, 2 of 4 (50%) patients with micrometastasis had recurrent disease, while 3 of 45 (6.7%) patients without micrometastasis developed recurrent disease. CONCLUSIONS: These preliminary data suggest that immunohistochemical detection of pelvic lymph nodes is more frequent in patients with LVSI and may identify patients needing adjuvant chemoradiation.