Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer?

Objective

To determine whether women with low-grade serous ovarian cancer (LGSOC) have personal and family histories of breast and ovarian cancer that are less suggestive of Hereditary Breast and Ovarian Cancer (HBOC), as compared to women with high-grade serous ovarian cancer (HGSOC).

Methods

A single institution, case-control retrospective review of medical records was conducted. Personal demographics, personal cancer history, and family history of breast and ovarian cancer of women with LGSOC were collected and compared to controls with HGSOC, which is known to be associated with HBOC.

Results

195 cases of LGSOC and 386 controls with HGSOC were included in the analysis. Women with LGSOC were significantly less likely to have a first- or second-degree relative with breast or ovarian cancer (p = 0.0016). Additionally, when the personal and family histories were quantified using the AMyriad BRC mutation prevalence tables, women with LGSOC had lower scores indicative of a less suggestive family history for HBOC (p = 0.027).

Conclusions

In this study, women with LGSOC had family histories that were less suggestive of HBOC compared to women with HGSOC, especially when the degree of relatedness of affected relatives was taken into account. By beginning to determine if LGSOC is part of the tumor spectrum seen in HBOC, this study is an important step towards refining hereditary cancer risk assessment for women with ovarian cancer.     

Is the combination with 2-methoxyestradiol able to reduce the dosages of chemotherapeutices in the treatment of human ovarian cancer? Preliminary in vitro investigations

PURPOSE OF INVESTIGATION: The endogenous estradiol metabolite, 2-methoxyestradiol (2ME), has been shown to be a potent inhibitor of cell growth and a strong anti-angiogenic substance. We investigated for the first time whether in vitro combinations of 2ME with various chemotherapeutic compounds may result in an additive inhibitory effect on the proliferation of human ovary cancer cells. METHOD: As a model two different human ovary cancer cell lines were used. All cell lines were incubated with equimolar concentrations of 2ME (0.8-25 microM) and the chemotherapeutics epirubicine, doxorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil and mafosfamide. Proliferation was measured after four days using the ATP-chemosensitivity test. RESULTS: For both ovary cancer cell lines a significant additive effect of 2ME with epirubicine and carboplatin was observed at the lower concentration range of these chemotherapeutic substances. CONCLUSION: 2ME is able to enhance the antiproliferative activity of certain chemotherapeutics at pharmacological relevant concentrations. This estradiol metabolite is currently in a phase II trial in patients with refractary metastatic breast cancer and the tolerability has been shown to be very good. The combination of 2ME with chemotherapeutics may therefore offer a new clinically relevant treatment regimen for hormone-dependent cancer.     

Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer?

OBJECTIVES: Clinicians often question when to start chemotherapy after patients undergo surgery for ovarian cancer. A major unproven concern is whether a long postoperative delay reduces the benefits of an extensive procedure and leads to disease progression. Our objectives were to evaluate the correlation between clinical and pathologic variables and to evaluate the effect of the "time to chemotherapy" (TTC) interval on survival. METHODS: We retrospectively studied data from 218 patients with International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4) who were consecutively treated between January 1, 1994, and December 31, 1998. RESULTS: Mean age at diagnosis was 64 years (range, 24-87 years; median, 65 years), and 206 patients received postoperative platinum-based chemotherapy. Mean TTC interval was 26 days (range, 7-79 days; median, 25 days). No correlation was found between operative time and TTC interval length (P=0.99). Age and performance of rectosigmoidectomy were correlated with longer TTC interval (P=0.009 and P=0.005, respectively), but TTC was not a predictor of overall survival (odds ratio, 1.00; 95% confidence interval, 0.98-1.01; P=0.85). Differences in TTC interval length (< or =17 days, 18-26 days, 27-33 days, or > or =34 days) did not affect survival (P=0.93). Even after categorizing patients by residual disease (<1 cm or > or =1 cm), no statistically significant effect of TTC on prognosis was identified. CONCLUSIONS: Concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer.     

The “Leuven” paclitaxel/carboplatin weekly regimen in patients with recurrent ovarian cancer,a retrospective study

ObjectiveTo evaluate the “Leuven” weekly paclitaxel/carboplatinum (TC) regimen in recurrent ovarian cancer in a retrospective study.MethodsEighteen courses of paclitaxel (60 mg/m²) and carboplatinum (AUC 2.7) were administered weekly. Platinum-resistance was defined as progression during or within 6 months after platinum-based chemotherapy.ResultsSixty-three patients were included with a median number of prior treatment regimens of 4 (range 0–10). Forty-three patients were platinum resistant and 20 were platinum sensitive (14 intermediate sensitive and 5 sensitive). One patient in the platinum resistant group and 2 patients in the platinum sensitive group achieved complete remission, 15 patients in the platinum resistant and 5 patients in the platinum sensitive group achieved partial remission according to RECIST. In the entire patient population evaluable for response (n = 62), the median progression free survival (PFS) was 6.7 months; the median overall survival (OS) was 9.7 months. Median PFS was 6 months for the platinum resistant and 8 months for the platinum sensitive group. The median OS was 9 months in the platinum resistant and 11 months in the platinum sensitive group.Toxicity was mostly bone marrow related with neutropenia grade 3/4 in 67% and neutropenic fever in 6% of patients. Dose reduction was necessary in 24% of patients. Nausea, vomiting and fatigue were the most frequent non-hematological side effects.ConclusionWeekly paclitaxel and carboplatin is an effective regimen for patients with recurrence of ovarian cancer with a response rate of 37% in platinum resistant disease and a manageable toxicity profile.     

The addition of topotecan to carboplatin and paclitaxel as first-line therapy for advanced ovarian cancer; is it possible only with peripheral blood stem cell support?

A phase I study was performed in order to evaluate the tolerability of the combination of fixed doses of carboplatin and paclitaxel and escalated doses of topotecan as first line chemotherapy for advanced epithelial ovarian cancer. Three stage III and one stage IV patients entered the study. The dose limiting toxicity (neutropenia and thrombocytopenia) was reached at the first dose level: paclitaxel 175 mg/m2 on day 1, carboplatin AUC 5 on day I and topotecan 0.5 mg/m2 daily from day 1 to day 3. We conclude that it is not possible to add topotecan to standard regimens of carboplatin and paclitaxel without bone marrow support.     

Inhibition of α4β1 integrin increases ovarian cancer response to carboplatin

Objective

The inability to successfully treat women with ovarian cancer is due to the presence of metastatic disease at diagnosis and the development of platinum resistance. Ovarian cancer metastasizes throughout the peritoneal cavity by attaching to and invading through the mesothelium lining the peritoneum using a mechanism that involves α4β1 integrin and its ligand (vascular cell adhesion molecule) VCAM-1. Integrin α4β1 expression on tumor cells is known to confer protection from therapy in other cancers, notably multiple myeloma. We evaluated the role of α4β1 integrin in response to platinum-based therapy in a mouse model of peritoneal ovarian cancer metastasis by treatment with a humanized anti-α4β1 integrin function-blocking antibody.

Methods

Integrin α4β1 expression on primary human ovarian cancer cells, fallopian tube and ovarian surface epithelia and fresh tumor was assessed by flow-cytometry. The therapeutic impact of anti-α4β1 treatment was assessed in murine models of platinum-resistant peritoneal disease and in vitro using the platinum resistant ovarian cancer cell lines.

Results

Treatment of tumor-bearing mice with human-specific α4β1 integrin function-blocking antibodies, anti-VCAM-1 antibody or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-α4β1 integrin or anti-VCAM-1 with carboplatin significantly reduced tumor burden. In vitro, the combination of carboplatin and anti-α4β1 integrin antibodies resulted in increased cell death and doubling time.

Conclusions

Our findings support a role for α4β1 integrin in regulating treatment response to carboplatin, implicating α4β1 integrin as a potential therapeutic target to influence platinum responsiveness in otherwise resistant disease.     

Fertility drugs and ovarian epithelial cancer: Is there a link?

Conclusions It should be noted that citing problems with epidemiologic studies is not the same as disproving their claims. However, it does cast doubt upon the validity and general applicability of their conclusions. The Rossing study strongly suggests an association between ovarian tumors and long-term use of clomiphene citrate. At the same time, it can safely be said that evidence that clomiphene or hMG therapy predisposes the patient to the development of ovarian epithelial carcinoma or any other ovarian tumor is extremely tenuous. Furthermore, there is no consistent physiologic principle (such as incessant ovulation) which can be applied to the use of these ovulation-inducing medications to suggest that they would be likely to cause such tumors.Therefore, physicians administering ovulation-inducing medications and contemplating the ramifications of a possible link between ovarian cancer and fertility medications are left with medicolegal considerations and with the simple principles of prudence and the dictum first to do no harm. As always, patients should be informed and offered alternatives. However, modification of the current practice of ovulation induction or ovarian superovulation on the basis of these epidemiologic studies does not seem warranted.The opinions presented in this column are those of its authors and do not necessarily reflect those of the journal and its editors, publisher, and advertisers.     

Is ovarian stimulation detrimental to the endometrium?

Ovarian stimulation in assisted reproduction technology produces lower implantation rates per embryo transferred than natural and ovum donation cycles, suggesting suboptimal endometrial development due to the abnormal concentrations of hormones used to recruit more oocytes. After the publication of several studies on the gene expression profile of endometrial receptivity in the natural cycle using microarray technology, researchers have investigated the impact of ovarian stimulation on the gene expression pattern of the endometrium. Ovarian stimulation cycles that use gonadotrophin-releasing hormone (GnRH) agonists and antagonists have been analysed in detail during the window of implantation to establish differences compared with the natural cycle. This paper reviews results obtained in different studies to elucidate the changes induced by the different protocols used in clinics. At the morphological level, no relevant alteration was observed in endometrial development in the early and mid-luteal phases in women undergoing ovarian stimulation following GnRH antagonist treatments. However, the gene expression pattern of the endometrium showed some differences. In addition, the endometrial development after GnRH antagonist mimics the natural endometrium more closely than after GnRH agonist at both the morphological (no relevant differences) and molecular level (only 23 genes dysregulated at high dose). Clinical implications of these differences should be analysed in more detail.     

Is there a role for HIPEC in ovarian cancer?

Hyperthermic intraperitoneal chemotherapy (HIPEC) is promoted by some as a standard treatment for peritoneal carcinomatosis of epithelial ovarian cancer (EOC) and other tumor entities, despite lack of robust data supporting this. Publicly available evidence addressing the value of HIPEC in EOC is rather inconclusive, revealing contradictory and inconsistent results while some studies even report harm to the patients from a higher morbidity. On this ground, we cannot recommend the implementation and use of HIPEC outside of a randomized clinical trial setting.     

Is maternal anxiety a barrier to exclusive breastfeeding?

Objective: To assess the association of maternal anxiety with nonadherence to exclusive breastfeeding.

Methods: This questionnaire-based study was conducted at a tertiary care teaching hospital in South India mothers with infants less than 6 months of age and not exclusively breastfeeding were interviewed and their demographic and clinical details were noted. The Iowa Infant Feeding Attitude Scale (IIFAS) and Hospital Anxiety and Depression Scale (HADS) were administered to these mothers.

Results: A total of 85 mother–infant dyads were included. The mean age of the mothers was 26 years and 57% were from urban areas. Among the additional feeds given, cow’s milk was the commonest (57.6%), followed by gripe water (28.2%) and formula feeds (16.5%). The mean HADS anxiety subscale score was 12.2 (±5.3) and HADS depression subscale score was 9.5 (±3.8). The mean score on IIFAS was 58.4 (±3.6) suggesting a relatively favorable attitude toward breastfeeding. On linear regression analysis, higher HADS depression score, lower birth weight and lower per capita income were independent predictors of poorer attitudes toward breastfeeding.

Conclusion: Maternal anxiety may be an independent risk factor for nonadherence to exclusive breastfeeding for the initial six months.     

Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with Paclitaxel-Platinum?

OBJECTIVE: Recurrent ovarian carcinoma is considered an incurable disease and second-line chemotherapy is administered for extension of survival and palliation. The impact of continued antineoplastic treatment in patients with stable disease without a demonstrable response is uncertain. The aim of this analysis was to assess the value of a stabilization of the tumor size in second-line chemotherapy as an indicator of survival. METHODS: Retrospective, single-institution study of 487 consecutive patients with primary epithelial ovarian carcinoma. Inclusion criteria: (1) FIGO stage IC-IV epithelial ovarian carcinoma; (2) first-line chemotherapy with Paclitaxel and a Platinum-compound; (3) refractory, persistent, or recurrent disease diagnosed by imaging methods; and (4) intravenous second-line chemotherapy with single Topotecan or Paclitaxel-Carboplatin. Univariate and multivariate analyses of survival with the World Health Organization (WHO) tumor response parameter included as a time-dependent variable were performed. RESULTS: The response rates were (N = 100): complete response (CR) 27%, partial response (PR) 14%, stable disease (SD) 41% and progressive disease (PD) 18%. In a multivariate Cox regression analysis of survival, SD was found to be an independent prognostic factor for survival and the death hazard ratio was 0.37 (SD versus PD; 95% CI: 0.16-0.86; P = 0.02). There was no statistically significant difference in survival between patients with PR and SD (P = 0.09). CONCLUSION: In second-line chemotherapy of ovarian cancer, patients demonstrating SD have a survival benefit compared to patients with PD measured by the WHO tumor response criteria.     

Is peritoneal cytology a prognostic factor of endometrial cancer confined to the uterus?

OBJECTIVE: The goal of this study was to investigate whether intraoperative peritoneal cytology serves as a prognostic factor in patients with the endometrial cancer limited to the disease confined to the uterus. METHODS: From patients with endometrial cancer treated at 2 facilities between 1988 and 2001, 307 patients were selected for retrospective investigation. To be included in this study, patients required (1) full surgical staging including total abdominal hysterectomy/bilateral salpingo-oophorectomy/retroperitoneal lymph node dissection/peritoneal cytology, (2) negative nodes, (3) disease localized to the uterus and (4) endometrioid subtype. RESULTS: The median duration of the follow-up period was 61 months (25th to 75th percentiles: 45 to 92 months). Peritoneal cytology was positive in 32 patients (10.4%). The 5-year survival rate of peritoneal-cytology-positive patients was 87%, significantly lower than that (97%) of cytology-negative patients (P = 0.011). The relationship between the clinicopathological factors including peritoneal cytology and the prognosis was investigated by univariate analysis, and peritoneal cytology positivity, age of 60 years or older, histologic grade (Grades 2 and 3), myometrial invasion of 1/2 or more and vascular invasion were significant prognostic factors (P < 0.05 in all). On multivariate analysis of these factors, peritoneal cytology positivity and histologic grade (Grade 2 and 3) were independent prognostic factors (P < 0.05 each). CONCLUSIONS: For the patients with endometrial cancer limited to the disease confined to the uterus in which accurate staging including retroperitoneal lymph node dissection was performed, peritoneal cytology may be an important prognostic factor.     

Is there a protective role of progestogens on the proliferation of human ovarian cancer cells in the presence of growth factors?

PURPOSE OF INVESTIGATION: The role of progestogens in the genesis of ovarian cancer remains unclear although a rather protective behaviour has been suggested. Epidemiological studies indicate a possible increase in the risk for combined estrogen/progestin as compared to estrogen alone. It is ambigious whether a difference exists within the various progestogens. Apart from sex steroids, growth factors play a crucial role in the genesis of ovarian cancer, although as yet little investigated. In the present study we have explored the effect of progesterone (P), medroxyprogesterone acetate (MPA) and norethisterone (NET) on the proliferation of human ovarian cancer cells alone and in the presence of growth factors. METHODS: For the experiments human ovarian cancer cells (OVCAR-3) were used. The progestogens were tested at the concentrations of 0.01 to 10 microM. The growth factor mixture consisted of EGF, FGF and IGF-I, each at a concentration of 10 pM. The incubation time was three or seven days. Proliferation rate was measured by an ATP-assay. RESULTS: After three days' incubation the growth factors induced an increase in the proliferation rate of about 50%. Progesterone alone did not show any significant change as compared to the control values, whereas NET and MPA elicited a significant increase at 1 and 10 microM and at 1 microM, respectively. In the presence of growth factors none of the progestogens was able to inhibit the proliferative stimulation. After seven days' incubation the growth factors still showed an increase of about 50%. MPA alone had an inhibitory effect at 10 microM, for NET and P no effects were observed. Again in the presence of growth factors no progestogen was able to show an inhibitory effect. CONCLUSION: Our results indicate that progestogens do not have a protective role on the growth of pre-existing ovarian cancer cells, at least in the presence of growth factors. Further investigations are worthwile to evaluate possible differences between the effect of the various progestogens.     

Is urinary incontinence a barrier to exercise in women?

OBJECTIVE: To describe the prevalence of urinary incontinence during exercise in women, estimate whether exercise intensity is related to leakage severity, and report women's assessments of incontinence as a barrier to exercise. METHODS: Questionnaires were mailed to 5,130 women aged 18-60 years drawn from National Family Opinion research panels. Physical activity levels were assessed by the International Physical Activity Questionnaire. Urinary incontinence, defined as involuntary leakage in the last 30 days, was assessed with the Sandvik Severity Index and a global measure of bother. Prevalence estimates were adjusted via post-stratification weighting. RESULTS: A total of 3,364 eligible women responded (68%), of whom 34.6% were insufficiently active (95% confidence interval [CI] 32.7-36.5%), 29.7% were sufficiently active (95% CI 27.9-31.5%), and 35.7% were highly active (95% CI 33.8-37.6%). Urinary incontinence prevalence was 34.3% (95% CI 32.5-36.1%). One in seven women experienced urinary leakage during physical activity; this was more common among highly active (15.9%) than less active women (11.8%) (P = .01). After adjusting for age, comorbidities, education, and race, women with very severe incontinence were 2.64 times (95% CI 1.25-5.55) more likely to be insufficiently active than continent women. Incontinence was a moderate or substantial barrier to exercise for 9.8% (95% CI 8.8-10.9%) of women. Of incontinent women, the proportion for whom incontinence was a moderate or substantial barrier to exercise increased with each severity category: 9.2%, slight; 37.8%, moderate; 64.6%, severe; and 85.3%, very severe (P < .01). CONCLUSION: Urinary incontinence is perceived as a barrier to exercise, particularly by women with more severe leakage.     

Weekly paclitaxel in heavily pretreated ovarian cancer patients: does this treatment still provide further advantages?

Objective

To evaluate the disease control rate (DCR) in heavily pretreated and relapsed ovarian cancer patients re-challenged with a weekly paclitaxel schedule and to establish whether a correlation between dose intensity, progression-free interval (PFI) and overall survival (OS) exists.

Methods

Retrospective data were collected from 30 heavily pretreated metastatic ovarian cancer patients who received 80?mg/m²/week paclitaxel regimen.

Results

The treatment was well tolerated and showed a DCR in 70% of the patients, with only one case of grade 3 hematological toxicity. One patient (3%) showed a complete response, 15 patients (50%) a partial response and five patients (17%) a stabilization of their disease. The regimen was mostly used as a fourth-line chemotherapy (range 2?C7). The median dose intensity in responding patients was 57.5?mg/m²/week and in those with progressive disease 49.7?mg/m²/week. (p?=?0.20). PFI and OS were increased in the responder patient groups with a log-rank test of 25.64 (p?<?0.001) and 15.10 (p?=?0.0001), respectively.

Conclusions

Weekly administration of paclitaxel was active and well tolerated as a salvage therapy for heavily pretreated ovarian cancer patients.