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Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG

PURPOSE Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.

Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen

OBJECTIVE The goal of this work was to study the role of transvaginal ultrasonography (TVUS) together with colorflow Doppler imaging (CFDI) in the detection of significant endometrial abnormalities induced by tamoxifen. METHODS Over a 6-year period, 304 women on tamoxifen as adjuvant therapy for breast cancer were recruited into the current study. Standard demographic data as well as duration of tamoxifen use were collected. Patients were assessed at study entry and at yearly intervals with TVUS together with CFDI. All patients had an endometrial biopsy at the time of study entry, and repeat endometrial evaluations were done subsequently only if there were abnormal ultrasound findings or the presence of irregular vaginal bleeding. All ultrasonic characteristics and Doppler flow measurements were recorded. Descriptive statistics were used to describe the study group. Logistic regression was used to identify significant treatment- and ultrasound-related factors associated with the presence of significant uterine pathology. RESULTS One thousand and sixty-one ultrasound assessments were performed on 304 patients over a 6-year period. The mean age was 52.33 (range, 29-79). Seventy-two percent of the patients were postmenopausal at the time of breast cancer diagnosis. The median concentrations of estrogen and progesterone receptor were 75 and 73 fmol/L, respectively. Fifty-eight percent of the patients had received cytotoxic chemotherapy. The mean duration of tamoxifen use was 48.2 months. Thirty-two percent of the ultrasound examinations had associated significant uterine pathology defined as conditions that required further medical or surgical investigation and treatment. However, 80% of the abnormalities represented benign polyps. Six cases of primary endometrial cancer were detected. All cases presented with irregular bleeding. No recurrence of disease was detected at a median follow-up of 48 months. One case of metastatic breast cancer to the uterus was encountered. By setting the endometrial thickness cutoff at more than 9 mm to represent significant abnormality in this patient population, the sensitivity was 63.3%, specificity was 60.4%, positive predictive value was 43.3%, and negative predictive value was 77.5%. To detect endometrial cancer, the endometrial thickness cutoff at 9 mm had a positive predictive value of only 1.4%. Logistic regression analysis showed only endometrial thickness greater than 9 mm (OR 3.99, CI = 1.26-12.65, P = 0.018) and spiral artery pulsatility index measurement (OR 4.18, CI = 1.25-13.92, P = 0.02) to be associated with significant uterine abnormalities. CONCLUSIONS Routine sequential ultrasound surveillance in asymptomatic women on tamoxifen is not useful because of its low specificity and positive predictive value. A significant portion of screened asymptomatic women would need to undergo needless surgical evaluations of their endometrium if widespread use of ultrasound is implemented in this patient population.

Preoperative identification of a suspicious adnexal mass: A systematic review and meta-analysis

OBJECTIVE To systematically review the existing literature in order to determine the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer. METHODS A review of all systematic reviews and guidelines published between 1999 and 2009 was conducted as a first step. After the identification of a 2004 AHRQ systematic review on the topic, searches of MEDLINE for studies published since 2004 was also conducted to update and supplement the evidentiary base. A bivariate, random-effects meta-regression model was used to produce summary estimates of sensitivity and specificity and to plot summary ROC curves with 95% confidence regions. RESULTS Four meta-analyses and 53 primary studies were included in this review. The diagnostic performance of each technology was compared and contrasted based on the summary data on sensitivity and specificity obtained from the meta-analysis. Results suggest that 3D ultrasonography has both a higher sensitivity and specificity when compared to 2D ultrasound. Established morphological scoring systems also performed with respectable sensitivity and specificity, each with equivalent diagnostic competence. Explicit scoring systems did not perform as well as other diagnostic testing methods. Assessment of an adnexal mass by colour Doppler technology was neither as sensitive nor as specific as simple ultrasonography. Of the three imaging modalities considered, MRI appeared to perform the best, although results were not statistically different from CT. PET did not perform as well as either MRI or CT. The measurement of the CA-125 tumour marker appears to be less reliable than do other available assessment methods. CONCLUSION The best available evidence was collected and included in this rigorous systematic review and meta-analysis. The abundant evidentiary base provided the context and direction for the diagnosis of early-staged ovarian cancer.

Quality-of-life issues in patients with ovarian cancer and their caregivers: a review.

Significant progress has been made towards the treatment of ovarian cancer resulting in longer median survival despite a persistent low cure rate. Relatively few studies have examined the impact of the cancer and its treatment on the patients and their caregivers due to the difficulty in the definition and measurement of the Quality of Life (QOL) concept. A review of the literature revealed significant alterations in the quality of life of ovarian cancer patients during treatment and long term follow ups. For the caregivers, it is important for health care providers to realize that: 1) caregivers are being asked to assume an increasing number of complex care giving tasks at home, 2) there exists a high proportion of unmet caregiver needs, 3) the care giving experience includes both positive and negative elements and, 4) perception of caregivers’ burden is positively linked to negative reactions to care giving. Supportive programs for patients and caregivers should be designed with these needs in mind. Future research should study the best way to incorporate results of quality of life assessments into routine treatment decision-making. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to outline the current data on QOL issues in patients with ovarian cancer, and to describe potential working definitions of QOL.

Sentinel lymph node biopsy in vulvar cancer: Systematic review, meta-analysis and guideline recommendations.

OBJECTIVES Traditionally, treatment for early stage vulvar cancer has included removal of the primary tumor and inguinofemoral lymph node dissection (IFLD). Sentinel lymph node biopsy (SLNB) has been proposed as an alternative to IFLD for early stage vulvar cancer patients. The aim of this project was to systematically review and assess the potential for harms and benefits with the SLNB procedure in order to make recommendations regarding the adoption of the procedure, selection of patients and appropriate technique and procedures. METHODS A working group with expertise in gynecologic oncology and health research methodology was formed to lead the systematic review and process of guideline development. MEDLINE, Embase and The Cochrane Database of Systematic Reviews were searched for relevant articles published up to September 2014. Outcomes of interest included detection, false negative, complication and recurrence rates and indicators related to pathology. Meta-analyses were conducted where appropriate. RESULTS The evidence-base of a previously published health technology assessment was adopted. An additional search to update the HTAs evidence base located three systematic reviews, and eleven individual studies that met the inclusion criteria. According to a meta-analysis, per groin detection rate for SLNB using radiocolloid tracer and blue dye was 87% [82-92]. The false negative rate with SLNB was 6.4% [4.4-8.8], and the recurrence rates with SLNB and IFLD were 2.8% [1.5-4.4] and 1.4% [0.5-2.6], respectively. An internal and external review process elicited concerns about the necessity of performing this procedure in an appropriate organizational context. CONCLUSION SLNB is recommended for women with unifocal tumors<4 cm and clinically non-suspicious nodes in the groin, provided that specific infrastructure and human resource needs are met. Some recommendations for appropriate techniques and procedures are also provided.

Management of a suspicious adnexal mass: a clinical practice guideline

QUESTIONS What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for malignancy? PERSPECTIVES In Canada in 2010, 2600 new cases of ovarian cancer were estimated to have been diagnosed, and of those patients, 1750 were estimated to have died, making ovarian cancer the 7th most prevalent form of cancer and the 5th leading cause of cancer death in Canadian women. Women with ovarian cancer typically have subtle, nonspecific symptoms such as abdominal pain, bloating, changes in bowel frequency, and urinary or pelvic symptoms, making early detection difficult. Thus, most ovarian cancer cases are diagnosed at an advanced stage, when the cancer has spread outside the pelvis. Because of late diagnosis, the 5-year relative survival ratio for ovarian cancer in Canada is only 40%. Unfortunately, because of the low positive predictive value of potential screening tests (cancer antigen 125 and ultrasonography), there is currently no screening strategy for ovarian cancer. The purpose of this document is to identify evidence that would inform optimal recommended protocols for the identification and surgical management of adnexal masses suspicious for malignancy. OUTCOMES Outcomes of interest for the identification question included sensitivity and specificity. Outcomes of interest for the surgical question included optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, and quality of life. METHODOLOGY After a systematic review, a practice guideline containing clinical recommendations relevant to patients in Ontario was drafted. The practice guideline was reviewed and approved by the Gynecology Disease Site Group and the Report Approval Panel of the Program in Evidence-based Care. External review by Ontario practitioners was obtained through a survey, the results of which were incorporated into the practice guideline. PRACTICE GUIDELINE These recommendations apply to adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic. IDENTIFICATION OF AN ADNEXAL MASS SUSPICIOUS FOR OVARIAN CANCER: Sonography (particularly 3-dimensional sonography), magnetic resonance imaging (mri), and computed tomography (ct) imaging are each recommended for differentiating malignant from benign ovarian masses. However, the working group offers the following further recommendations, based on their expert consensus opinion and a consideration of availability, access, and harm: Where technically feasible, transvaginal sonography should be the modality of first choice in patients with a suspicious isolated ovarian mass.To help clarify malignant potential in patients in whom ultrasonography may be unreliable, mri is the most appropriate test.In cases in which extra-ovarian disease is suspected or needs to be ruled out, ct is the most useful technique.Evaluation of an adnexal mass by Doppler technology alone is not recommended. Doppler technology should be combined with a morphology assessment.Ultrasonography-based morphology scoring systems can be used to differentiate benign from malignant adnexal masses. These scoring systems are based on specific ultrasound parameters, each with several scores base on determined features. All evaluated scoring systems were found to have an acceptable level of sensitivity and specificity; the choice of scoring system may therefore be made based on clinician preference.As a standalone modality, serum cancer antigen 125 is not recommended for distinguishing between benign and malignant adnexal masses.Frozen sections for the intraoperative diagnosis of a suspicious adnexal mass is recommended in settings in which availability and patient preference allow. SURGICAL PROCEDURES FOR AN ADNEXAL MASS SUSPICIOUS FOR MALIGNANCY: To improve survival, comprehensive surgical staging with lymphadenectomy is recommended for the surgical management of patients with early-stage ovarian cancer. Laparoscopy is a reasonable alternative to laparotomy, provided that appropriate surgery and staging can be done. The choice between laparoscopy and laparotomy should be based on patient and clinician preference. Discussion with a gynecologic oncologist is recommended. Fertility-preserving surgery is an acceptable alternative to more extensive surgery in patients with low-malignant-potential tumours and those with well-differentiated surgical stage i ovarian cancer. Discussion with a gynecologic oncologist is recommended.

Initial Evaluation and Referral Guidelines for Management of Pelvic/Ovarian Masses

OBJECTIVES To optimize the management of adnexal masses and to assist primary care physicians and gynaecologists determine which patients presenting with an ovarian mass with a significant risk of malignancy should be considered for gynaecologic oncology referral and management. OPTIONS Laparoscopic evaluation, comprehensive surgical staging for early ovarian cancer, or tumour debulking for advanced stage ovarian cancer. OUTCOMES To optimize conservative versus operative management of women with possible ovarian malignancy and to optimize the involvement of gynaecologic oncologists in planning and delivery of treatment. EVIDENCE Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified by searching the web sites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RECOMMENDATIONS 1. Primary care physicians and gynaecologists should always consider the possibility of an underlying ovarian cancer in patients in any age group who present with an adnexal or ovarian mass. (II-2B) 2. Appropriate workup of a perimenopausal or postmenopausal woman presenting with an adnexal mass should include evaluation of symptoms and signs suggestive of malignancy, such as persistent pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, and difficulty eating. In addition, CA125 measurement should be considered. (II-2B) 3. Transvaginal or transabdominal ultrasound examination is recommended as part of the initial workup of a complex adnexal/ovarian mass. (II-2B) 4. Ultrasound reports should be standardized to include size and unilateral/bilateral location of the adnexal mass and its possible origin, thickness of septations, presence of excrescences and internal solid components, vascular flow distribution pattern, and presence or absence of ascites. This information is essential for calculating the risk of malignancy index II score to identify pelvic mass with high malignant potential. (IIIC) 5. Patients deemed to have a high risk of an underlying malignancy should be reviewed in consultation with a gynaecologic oncologist for assessment and optimal surgical management. (II-2B).

The Definition of Optimal Inguinal Femoral Nodal Dissection in the Management of Vulva Squamous Cell Carcinoma

ObjectivesTo reject the hypothesis that the number of nodes removed at time of surgical staging for vulva cancer is not an important prognostic factor.MethodsRetrospective chart reviews were carried out from 1980-2004 to identify patients with squamous cell vulva carcinoma treated with radical vulvectomy and bilateral inguinal femoral lymph node dissection. Patients’ demographics, disease characteristics, the number of lymph nodes removed at surgery, and standard oncologic outcomes were recorded. Cox proportional hazard models were built to model times to clinical progression and death using predictor variables of: age, tumor size and maximum depth of invasion, resection margin status, and total number of nodes removed.ResultsFifty-eight patients were identified. The median lesion size was 3.5 cm. The median depth of invasion was 7.5 mm. The 20th percentile for total number of lymph nodes removed was 10. Adjuvant radiation therapy was given in 31% of patients. At a median follow-up of 37 months, recurrence was observed in 17 patients (29.3%). Cox regressions showed the total number of nodes removed less than 10 to be the only significantly predictive of shorter time to first progression (HR = 12.88, 95% CI = 1.47-112.89, P = .021) and shorter disease specific survivals (HR = 11.41, 95% CI = 2.21-58.86, P = .004) (HR, hazard ratio; CI, confidence interval).ConclusionThe total number of nodes removed at time of surgical staging is an independent survival prognostic factor. A total of at least 10 nodes from a bilateral dissection can be used to define an optimal evaluation.

Supportive Care Needs After Gynecologic Cancer: Where Does Sexual Health Fit in?

DESIGN Descriptive, cross-sectional study. SETTING Follow-up clinic of a gynecologic oncology program in a regional cancer center. SAMPLE 113 women treated for gynecologic cancer. METHODS Data were collected using standardized instruments and analyzed through descriptive and correlation statistics. MAIN RESEARCH VARIABLES Supportive care needs, sexual health needs, vaginal changes, desire for help, and socio-demographic and medical factors. FINDINGS Forty percent of the sample was worried about the status of their sex life and many wished to meet one-on-one with a health professional or to receive written information. Younger age, premenopausal status at diagnosis, and lower sexual satisfaction and more vaginal changes after treatment were associated with greater sexual health needs and desire for help. CONCLUSIONS Several sexual health needs were among the highest reported supportive care needs. Certain subgroups may report higher needs and desire for help; this domain merits additional research. Needs were extremely diverse, reflecting the use of an individual approach to screening for and meeting survivor needs. IMPLICATIONS FOR NURSING Personal perceptions of the implications and meaning of sexual health and vaginal changes create the subjective experience of a need. Discussions of the womens perceptions of their needs and their views of healthy sexuality will help develop effective treatment plans.

Surgical management of a suspicious adnexal mass: A systematic review

OBJECTIVE To systematically review the existing literature in order to determine the optimal recommended protocols for the surgical management of adnexal masses suspicious for apparent early stage malignancy. METHODS A review of all systematic reviews and guidelines published between 1999 and 2009 was conducted as a first step. After the identification of two systematic reviews on the topic, searches of MEDLINE for studies published since 2004 were also conducted to update and supplement the evidentiary base. RESULTS The updated literature search identified 31 studies that met the inclusion criteria. A bivariate random effects analysis of 15 frozen section diagnosis studies yielded an overall sensitivity of 89.2% (95% CI, 86.3 to 91.5%) and specificity of 97.9% (95% CI, 96.6 to 98.7%). The surgical evidence suggests that systematic lymphadenectomy and proper surgical staging improve survival. Conservative fertility-preserving surgical approaches are an acceptable option in women with low malignant potential tumours. The accuracy and the adequacy of surgical staging by laparotomy or laparoscopic approaches appear to be comparable, with neither approach conferring a survival advantage. Intraoperative tumour rupture was indeed reported to occur more frequently in patients undergoing laparoscopy versus laparotomy in two retrospective cohort studies. CONCLUSIONS The best available evidence was collected and included in this rigorous systematic review. The abundant evidentiary base provided the context and direction for the surgical management of adnexal masses suspicious for apparent early stage malignancy.