Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

Severe craniosynostosis in an infant with deletion 22q11.2 syndrome.

We report a male infant with 22q11.2 deletion syndrome and very severe multi-sutural craniosynostosis associated with increased intracranial pressure, marked displacement of brain structures, and extensive erosion of the skull. While uni- or bi-sultural craniosynostosis is a recognized (though relatively uncommon) feature of 22q11 deletion syndrome, a severe multi-sutural presentation of this nature has never been reported. SNP Microarray was otherwise normal and the patient did not have common mutations in FGFR2, FGFR3, or TWIST associated with craniosynostosis. While markedly variable expressivity is an acknowledged feature of deletion 22q11 syndrome, herein we also consider and discuss the possibility that this infant may have been additionally affected with an undiagnosed single gene disorder.

The risk of nodal metastasis in early adenocarcinoma of the uterine cervix.

A functional and widely accepted definition of microinvasive cervical adenocarcinoma remains elusive. The purpose of this study was to determine at which depth of invasion the likelihood of lymph node metastasis or disease recurrence was so small that conservative surgery could be considered appropriate. Charts of patients with adenocarcinoma of the cervix (ACC) who underwent radical hysterectomy and pelvic lymphadenectomy (n = 98) at Indiana University Medical Center from 1987 to 1998 were retrospectively reviewed. Patients with stage IA1-IB1 lesions were included in the study. Patients treated with preoperative radiotherapy were excluded. Pathologic parameters evaluated included histologic type, depth of stromal invasion (DOI), and the presence of lymphatic vascular space invasion, or lymph node metastases. The patient median age was 39 years (20-65). The median time of follow-up was 30 months (4-124). Lymph node metastases were found in ten patients and 11 developed recurrences. The precise DOI could be measured in 84 patients. Of the 48 patients with cancers with a DOI 5 mm had nodal metastases (P = 0.00069). None of these 48 patients with a tumor DOI 5 mm developed recurrent disease (P = 0.0048). The risk of nodal metastases and recurrence is so low in patients with ACC and DOI

Effect of carbon dioxide on human ovarian carcinoma cell growth.

OBJECTIVE: Laparoscopy may be associated with increased risk of ovarian carcinoma wound metastases. This study was designed to determine whether carbon dioxide exposure increases the growth of human ovarian cancer cells in vitro. STUDY DESIGN: Immortalized ovarian epithelial carcinoma cell (SKOV-3 cell line) cultures were exposed to carbon dioxide, nitrous oxide, or culture media with decreased pH for up to 3 hours. Cell growth was determined with the use of a spectrophotometric assay, and the results were compared with control cells by paired t tests and linear regressions analysis. RESULTS: Carbon dioxide exposure increased SKOV-3 cell growth by 52% after 4 days in culture. The increased cell growth had a linear relationship to the length of carbon dioxide exposure. Cells that were exposed to either nitrous oxide or media with pH 6.3 showed a trend toward decreased growth. CONCLUSION: Carbon dioxide exposure increases the in vitro growth of human ovarian carcinoma cells by an effect that is independent of the carbon dioxide-related decrease in the culture media pH.

Cervical primitive neuroectodermal tumor.

BACKGROUND: Primitive neuroectodermal tumors (PNETs) are rare and potentially aggressive malignancies. CASE: A 24-year-old woman in her eighth week of pregnancy presented with a cervical mass. Tissue biopsy demonstrated poorly differentiated carcinosarcoma with neuroendocrine features. Immunohistochemical studies confirmed the diagnosis of PNET. Treatment included alternating courses of cyclophosphamide, adriamycin, vincristine (CAV) and ifosfamide, etoposide (IE). A radical hysterectomy with bilateral ovarian transposition and periaortic lymphadenectomy was performed with postoperative chemotherapy and radiotherapy. The patient remains disease free 2 years from therapy. CONCLUSION: This is a rare case of cervical PNET occurring in a pregnant patient. A review of the literature indicates that cervical PNET is distinguishable from uterine PNET. This tumor affects younger women and may have a different histogenesis. Pregnancy should not delay diagnosis of this potentially aggressive tumor.

Expression and subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in epithelial ovarian cancer.

OBJECTIVE: To determine if p27(Kip1) expression was altered in epithelial ovarian cancers as compared to normal ovarian surface epithelial (NOSE) cells and to determine if subcellular localization of p27(Kip1) was an important feature. METHODS: Thirteen tumor samples (1 Stage IC [early] and 12 Stage III/IV [advanced]) from patients with epithelial ovarian cancer and five NOSE samples were evaluated. Samples were surgically dissected to obtain an enriched population (90%) of cancer cells. The level of p27(Kip1) protein expression was determined by Western blot analysis. Actin was used as a loading control, and results were quantified by scanning densitometry using the ratio of the p27(Kip1) signal to the actin signal for comparison. To evaluate the subcellular localization of p27(Kip1), immunocytochemical staining was performed. Clinical pathological parameters were correlated to nuclear p27(Kip1) staining to establish if any association existed. RESULTS: When comparing the expression of p27(Kip1) between NOSE and ovarian cancer samples, only 2 of 13 ovarian cancer samples had altered p27(Kip1) expression. No correlation was found between the expression level of p27(Kip1) on Western blot and clinical pathological correlates. While no correlation between expression level of p27(Kip1) and subcellular localization was found, decreased nuclear staining (1+) was associated with shorter survivals using the log-rank test (P < 0.001). More importantly, in all tumor samples examined under the microscope, no nuclear p27(Kip1) staining was noted in cells that were undergoing mitosis. CONCLUSIONS: p27(Kip1) protein degradation may not be modified in ovarian cancer cells undergoing mitosis. Altered expression of p27(Kip1) is not an overwhelming feature in certain epithelial ovarian cancers. Decreased nuclear staining of p27(Kip1) is associated with poor survival in some epithelial ovarian cancers.

DNA methylation and ovarian cancer. I. Analysis of CpG island hypermethylation in human ovarian cancer using differential methylation hybridization.

OBJECTIVE: The aim of this study was to examine CpG island methylation patterns in ovarian cancer and determine whether epigenetic information can be related to clinical data of patients. CpG island (CpGI) hypermethylation is commonly associated with cancer progression, but little is currently known about the role of methylation in ovarian cancer. METHODS: Differential methylation hybridization (DMH) analysis at 742 loci was performed to determine methylation signatures for 20 primary epithelial ovarian carcinomas (Stages II, III, and IV adenocarcinomas, serous papillary), 6 ovarian cancer cell lines, and normal ovarian surface epithelial cells. RESULTS: Between 23 and 108 methylated CpGIs were seen in the ovarian carcinomas. Fewer (P < 0.05) methylated CpGIs were observed in the ovarian cancer cell lines; however, a number of CpGIs were commonly hypermethylated in both the cell lines and the tumor samples. A methylation signature, consisting of frequently (P < 0.05) methylated CpGIs, was determined for the samples. The observed pattern of methylation in ovarian cancers included several (11) CpGI tags that were previously reported to be hypermethylated in human breast cancer. CONCLUSIONS: Epigenetic signatures in ovarian cancer were determined using DMH. This proof-of-concept study lays the foundation for genome-wide screening of methylation to examine epigenotype-phenotype relationships in ovarian cancer.

DNA methylation in ovarian cancer. II. Expression of DNA methyltransferases in ovarian cancer cell lines and normal ovarian epithelial cells.

OBJECTIVE: The aim of this study was to investigate whether expression of the enzymes that catalyze cytosine CpG island methylation, DNA methyltransferases, DNMT1, DNMT3a, and DNMT3b is altered in human ovarian cancer. Aberrations in DNA methylation are common in cancer and have important roles in tumor initiation and progression. Tumors that display frequent and concurrent inactivation of multiple genes by methylation are designated as having a CpG Island methylator phenotype, or CIMP. To date, colon, gastric, and most recently ovarian cancers meet the CIMP criteria for cancer. We hypothesized that altered expression of DNA methyltransferases can result in hypermethylation events seen in CIMP cancers. METHODS: DNMT1, DNMT3a, and DNMT3b mRNA levels in eight ovarian cancer cells lines (Hey, HeyA8, HeyC2, OVCAR-3, SK-OV-3, PA-1, A2780, and A2780-P5) were compared to DNMT expression in normal ovarian surface epithelial cells using semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: In HeyA8 and HeyC2 ovarian cancer cells, DNMT1 expression levels were up to threefold higher (P < 0.05) than in normal ovarian surface epithelial cells. SK-OV-3 and PA-1 displayed increased DNMT3b expression (P < 0.05) compared to normal ovarian surface epithelial cells. Transcript levels for DNMT3a, however, were similar in cancer and normal ovarian cells. CONCLUSIONS: We observed differential expression of the DNMT genes in some ovarian cancer cell lines and conclude that alterations in DNMT expression might contribute to the CIMP phenotype in ovarian cancer. However, based on the lack of aberrant DNMT expression in some of the cancer cell lines examined, we further suggest that another mechanism(s), in addition to DNMT overexpression, accounts for methylation anomalies commonly observed in ovarian cancer.

Evaluation of recombinant human interleukin-12 in patients with recurrent or refractory ovarian cancer: a gynecologic oncology group study.

Objective. The goal of this study was to estimate the antitumor activity and toxicity of recombinant human interleukin-12 (rhIL-12) in patients with recurrent or refractory epithelial ovarian cancer. Methods. From December 1997 to March 1999, patients with recurrent or refractory epithelial ovarian cancer were entered on a Gynecologic Oncology Group phase II study of intravenous rhIL-12. All patients had measurable disease, had a performance status of 0-2, and had failed first-line platinum-based chemotherapy regimen. Eligible patients received rhIL-12, 250 ng/kg IV bolus, as a single dose on Day 1 followed by a 2-week rest period, with subsequent cycles administered daily for 5 days followed by a 16-day rest period per cycle, until disease progression or adverse effects prohibited further therapy. Results. Twenty-eight patients were entered and evaluable for toxicity, while 26 were evaluable for response. The median age was 59.5 years (range: 45-77). The median number of cycles was 2 (range: 1-9). There were no complete responders; however, one patient (3.8%) was a partial responder and 13 patients (50%) had stable disease. Grade 4 myelotoxicity occurred in 21% of patients. Two patients experienced capillary leak syndrome: one grade 2 and one grade 4. Conclusion. As a single agent, rhIL-12 is tolerable and shows a low response rate in recurrent epithelial cancer with measurable disease.

A phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix--a Gynecologic Oncology Group Study.

PURPOSE: The Gynecologic Oncology Group performed a Phase II study to determine the response rate of Pyrazoloacridine (PZA) in patients with advanced, persistent or recurrent squamous carcinoma of the cervix. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over three hours every three weeks. RESULTS: Among 21 evaluable patients, there were no complete and one (4.2%) partial response. The major toxicities were hematologic. CONCLUSION: PZA at the dose and schedule employed has insignificant activity in this population.

Location of the ureters in relation to the uterine cervix by computed tomography.

OBJECTIVE: Our aim was to determine the distance of the ureter from the cervix and the influence of age and weight on this distance. STUDY DESIGN: The distance of the ureter from the uterine cervix was determined by evaluating the computed pelvic tomograms from 52 women. Age and body mass index were compared to this distance by means of regression analysis. RESULTS: At the most dorsal reflection of the ureter, the average distance from ureter to cervical margin was 2.3 +/- 0.8 cm (range, 0.1-5.3 cm). There was no relationship to age, but there was a linear relationship between this distance and body mass index (R2 = 0.075; P = .049); thus the ureter was slightly more proximal to the cervical margin in heavier women. CONCLUSIONS: In women with apparently normal pelvic anatomy, the average distance between the ureter and cervix is >2 cm. The finding that this distance is <0.5 cm in 12% of the women studied may explain the relatively common occurrence of ureteral injury during hysterectomy. The relationship between body mass index and location is clinically insignificant.

Regulation of invasion of epithelial ovarian cancer by transforming growth factor-beta.

OBJECTIVE: The metastatic process in epithelial ovarian cancer is thought to involve surface shedding and subsequent dissemination of ovarian cancer cells, facilitated by localized proteolysis at the interface between ovarian cancer cells and peritoneal surfaces. The factors regulating the metastatic process, however, are not well understood. Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that elicits numerous cellular effects pertinent to the metastatic process. The purpose of this study was to evaluate the regulatory role of TGF-beta on metastasis in ovarian cancer. METHOD: We evaluated the effect of TGF-beta on the metastatic characteristics (adhesion, invasion, motility, proteolysis) of five ovarian cancer cell lines (DOV-13 and OVCA 420, 429, 432, and 433), two short-term primary ovarian cancer cell cultures (OVCA 10 and OVCA 208), and five normal ovarian surface epithelial (NOSE) cell cultures (OSE 133, 185, 186, 188, and 189). The effect of TGF-beta on invasion and proteolysis was quantified using a modified Boyden chamber invasion assay, zymography, a coupled colorimetric activity assay, and an HPLC-based quantitation of synthetic substrate cleavage. RESULTS: TGF-beta significantly increased invasion in five of seven ovarian cancer cell lines in amounts ranging from 2- to 20-fold. In contrast, TGF-beta significantly decreased invasion in two of five NOSE isolates by 50 to 80% and had no significant effect on invasion in three. TGF-beta treatment increased matrix metalloproteinase (MMP) expression in OVCA 420 and 433 and DOV-13, resulting in MMP-dependent collagen cleavage and invasive activity. Addition of the MMP inhibitor GI12947 neutralized the enhancing effect of TGF-beta on invasion. TGF-beta had no effect on ovarian cancer cell motility and only increased adhesion in DOV-13. CONCLUSIONS: These data suggest that TGF-beta may enhance the invasiveness of ovarian cancers through induction of MMP activity.

Cardiac electron-beam CT in children undergoing surgical repair for pulmonary atresia.

PURPOSE: To study whether electron-beam computed tomography (CT) is as accurate as conventional angiocardiography for the characterization of the true pulmonary arteries and the aortopulmonary collateral vessels in children undergoing surgical correction for pulmonary atresia. MATERIALS AND METHODS: Twenty-three children with pulmonary atresia underwent 48 cardiac-triggered dynamic contrast material-enhanced electron-beam CT studies. Correlation was made with surgical findings in all patients and with 34 cineangiocardiograms. Data from reconstructed electron-beam CT images and cineangiocardiograms were reviewed for the presence, caliber, and origin of true pulmonary arteries and aortopulmonary collateral vessels; for stenosis; for thrombosis; and for the patency of vascular conduits and shunts. RESULTS: Electron-beam CT was more sensitive than angiography in the identification of hypoplastic and/or nonconfluent branch pulmonary arteries, coronary anomalies, conduit and shunt thrombosis, and other postoperative complications, but it was less sensitive in the demonstration of stenoses at collateral vascular origins and anastomoses. Overall test parameters for electron-beam CT and angiography to characterize pulmonary vascularity were similar (sensitivity, 0.94 vs 0.90; specificity, 0.99 for both; accuracy, 0.97 vs 0.95). Three-dimensional reconstructions, although they were helpful in conveying electron-beam CT findings to referring cardiologists and surgeons, did not add diagnostic information to that displayed on images of the transverse sections. CONCLUSION: Electron-beam CT complements conventional diagnostic angiocardiography in preoperative evaluation, especially in the detection of hypoplastic pulmonary arteries. It is well suited for postoperative shunt surveillance.

FIGO stage IIIC endometrial carcinoma with metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables, and failure patterns following adjuvant radiation therapy.

OBJECTIVES: This study was undertaken to evaluate the prognostic significance of isolated positive pelvic lymph nodes on survival and to analyze other prognostic variables, overall survival, and failure patterns in surgically staged endometrial carcinoma patients with positive pelvic lymph nodes and negative para-aortic lymph nodes following radiation therapy (RT). METHODS: Between January 1, 1987, and December 31, 1997, 782 women underwent primary treatment for uterine cancer at Indiana University Medical Center. Through a review of the medical records, we identified 58 patients with pathologic stage IIIA, 27 patients with pathologic stage IIIB, and 77 patients with pathologic stage IIIC endometrial carcinoma. Patients with pathologically positive or unsampled para-aortic lymph nodes and patients who received preoperative radiation therapy were excluded, leaving a study group of 17 patients with nodal metastases confined to pelvic lymph nodes. Thirteen patients received adjuvant pelvic RT using AP-PA or four-field technique. A median dose of 5040 cGy was delivered. Four patients received whole abdominal irradiation (WAI) delivering a median dose of 3000 cGy. Two patients received vaginal cuff boosts of 1000 and 3560 cGy to 0.5 cm from the vaginal surface mucosa via Cs-137 brachytherapy. Two patients also received adjuvant chemotherapy (cis-platinum and doxorubicin) and/or hormonal therapy (megestrol acetate). Disease-free and overall survivals were estimated using the Kaplan-Meier method of statistical analysis and prognostic variables were analyzed using the log-rank test. RESULTS: With a median follow-up of 51 months the actuarial 5-year disease-free survival was 81% and the actuarial 2-year and 5-year overall survival rates were 81 and 72%, respectively. Univariate analysis revealed that positive peritoneal cytology in conjunction with positive pelvic lymph nodes imparts a greater risk of recurrence and decreased overall survival. There were no pelvic and/or upper abdominal failures, but there were recurrences in the para-aortic lymph nodes (two patients) and distantly (two patients). CONCLUSION: Surgery followed by postoperative pelvic RT is a viable treatment option for pathologically staged stage IIIC endometrial carcinoma with disease confined to the pelvic lymph nodes. Failures in the para-aortic region suggest a possible role for extended-field RT. Patients with positive peritoneal cytology in conjunction with nodal metastasis fared poorly with pelvic RT. Studies evaluating the efficacy of WAI are ongoing. Finally, substages within FIGO stage IIIC are recommended in an effort to better understand and define treatment strategies which might be appropriate for these patients.

Trisomy 21 associated with ovarian dysgerminoma.

A 13-year-old G(0)P(0) white female with trisomy 21 presented with a complex pelvic mass. She underwent resection of the mass and complete staging for what was found to be a stage IIIC completely resected dysgerminoma. She was treated with three cycles of bleomycin, etoposide, and cisplatin chemotherapy and remains free of disease 1 year later. This association is presented as a rare case that may illustrate the relative increase in germ cell neoplasms in female patients with Down's syndrome. While the association of seminoma with Down's syndrome has been documented in a number of cases in males, the female counterpart of this tumor, dysgerminoma, in trisomy 21 has been reported quite infrequently. The potential for germ cell tumors in both male and female trisomy 21 is therefore illustrated.

Transforming growth factor-beta differentially inhibits epithelial ovarian carcinoma cells from primary and metastatic isolates without up-regulation of p21WAF1.

BACKGROUND: Transforming growth factor-beta (TGF-beta) is known to inhibit primary epithelial ovarian carcinoma cells. The mechanism by which this inhibitory response is achieved is poorly understood. Furthermore, whether this response is consistent in cells from metastatic sites compared with the primary site cells is unknown. The authors wanted to determine whether TGF-beta differentially inhibited ovarian carcinoma cells from primary tumor sites compared with metastatic sites and to establish whether this response was associated with up-regulation of p21WAF1 or overexpression of p53. METHODS: Tumor cells were purified from primary and metastatic sites in five patients with advanced epithelial ovarian carcinoma. TGF-beta effect at concentrations of 10, 1, and 0.1 ng/mL was determined by tritiated thymidine incorporation assay. Expression of p21WAF1 was determined by Northern and slot blot analysis. p53 was detected by immunocytochemistry. RESULTS: Metastatic tumor isolates were more responsive to the inhibitory effect of TGF-beta compared with their corresponding primary tumor isolates at 0.1 ng/mL. Increasing TGF-beta concentration conferred no additional inhibitory effect on the metastatic isolates; however, a dose-related phenomenon was observed in primary tumor isolates. p21WAF1 mRNA was up-regulated in only 2 of 10 primary and metastatic isolates. There was no correlation between TGF-beta responsiveness, p21WAF1 up-regulation, and p53 overexpression. CONCLUSIONS: Differential inhibition was observed between primary and metastatic tumor isolates. p21WAF1 up-regulation and p53 overexpression were not major modulators in TGF-beta regulation of primary and metastatic tumor growth in early passaged ovarian carcinoma cells.

Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies. METHODS: Patients with incompletely resected Stages II-IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2 x 9 weeks for a maximum dose of

Location of the transverse colon in relationship to the umbilicus: implications for laparoscopic techniques.

STUDY OBJECTIVE: To establish the location of the transverse colon in relationship to the umbilicus, and determine if it varies as a function of patient height or weight. DESIGN: Retrospective review of computed tomograms (CT) of the abdomen (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Sixty-seven women with normal abdominal anatomy. INTERVENTION: Review of abdominal CT scans. MEASUREMENTS AND MAIN RESULTS: The relative relationships of the transverse colon and umbilicus were compared with age, height, weight, and body mass index (BMI = kg/m2) using multiple regression analysis. Average location of the superior margin of the transverse colon was 4.6 cm (95% CI 3.5-5.7 cm) above the umbilicus. In nine (13%) women it was below the umbilicus. The colon was below the umbilicus in 25% of nonobese women (BMI <25 kg/m2). CONCLUSION: Because the transverse colon lies below the umbilicus in more than 10% of women, injury to it may be an uncommon yet unavoidable complication of laparoscopy.

Phase 2 trial of single agent ifosfamide/mesna in patients with platinum/paclitaxel refractory ovarian cancer who have not previously been treated with an alkylating agent.

Ifosfamide has been shown to possess modest activity in patients with platinum/cyclophosphamide refractory ovarian cancer. Current standard initial chemotherapy for ovarian cancer does not include an alkylating agent (paclitaxel substituting for cyclophosphamide). To evaluate the activity of ifosfamide in patients with refractory ovarian cancer who had not previously received an alkylating agent, 21 patients with platinum/paclitaxel refractory disease were treated with the drug as a single agent (1.8 g/m2/day x 3 days, with treatment repeated every 28 days). Treatment was reasonably well tolerated in most patients, although 1 individual was removed from study secondary to neurotoxicity. One patient exhibited an objective response of measurable disease, while a second individual had a major decrease in CA-125 levels (no measurable disease present) following therapy. An additional patient experienced disappearance of severe pelvic pain following treatment but failed to meet the criteria for a partial response. We conclude that ifosfamide has modest activity in platinum/paclitaxel refractory ovarian cancer. However, the level of effectiveness does not appear to be increased in individuals who are alkylating-agent naive, compared to previously reported experience in patients with prior exposure to this class of cytotoxic drugs (10-15% response rate).

Gynecologic cancers metastatic to the breast.

BACKGROUND: We report a series of gynecologic cancers metastatic to the breast, illustrating the diagnostic and prognostic implications of this rare event. STUDY DESIGN: By reviewing the gynecologic oncology data base, we identified 10 women with gynecologic cancer metastatic to the breast who were treated at Indiana University School of Medicine between August 1978 and February 1995. Medical records were reviewed for pertinent data concerning the presentation, evaluation, and treatment of the primary gynecologic malignancy and the metastatic breast tumor. RESULTS: The mean patient age was 56.8 years (range, 30-80 years). The most common gynecologic malignancy was ovarian cancer (five patients), followed by cervical cancer (two patients) and cancers of the vagina, endometrium, or peritoneum (one patient each). A palpable solitary breast mass was found in 8 of 10 patients (80%), and the upper outer quadrant of the breast was the most common site of tumor involvement. One woman presented with examination findings resembling inflammatory breast cancer, and one patient presented with multiple firm subcutaneous nodules. Despite further treatment, which in all cases consisted of systemic chemotherapy, 83% of the patients died with a breast metastasis within 1 year of presentation. CONCLUSIONS: Secondary breast malignancy should be suspected in any patient with a breast tumor and a known history of gynecologic cancer. A breast metastasis implies widespread tumor dissemination and a poor prognosis. Radical breast surgery should be avoided.