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Objective To evaluate the cost-effectiveness of bevacizumab in recurrent/persistent and metastatic cervical cancer using recently reported updated survival and toxicology data. Methods A Markov decision tree based on the Gynecologic Oncology Group 240 randomized trial was created. The 2013 MediCare Services Drug Payment Table and Physician Fee Schedule provided costs. In the 5-year model subjects transitioned through the following states: response, progression, minor complications, severe complications, and death. Patients experiencing a health utility per month according to treatment effectiveness were calculated. Because cervical cancer survival is measured in months rather than years, results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY), adjusted from a baseline of having advanced cervical cancer during a month. Results The estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, adding $73,791 per 3.5 months (0.29 year) of life gained, resulting in an incremental cost-effectiveness ratio (ICER) of $21.083 per month of added life. The ICER increased to $5775 per month of added life and $24,597/QALmonth ($295,164/QALY) due to the smaller difference in QALmonths. With 75% bevacizumab cost reduction, the ICER is $6737/QALmonth ($80,844/QALY), which translates to $23,580 for the 3.5 month (0.29 year) gain in OS. Conclusions Increased costs are primarily related to the cost of drug and not the management of bevacizumab-induced complications. Cost reductions in bevacizumab result in dramatic declines in the ICER, suggesting that cost reconciliation in advanced cervical cancer may be possible through the availability of biosimilars, and/or less expensive, equally efficacious anti-angiogenesis agents.

Background: GOG 240 was a practice-changing randomised phase 3 trial that concluded that chemotherapy plus bevacizumab for advanced cervical cancer significantly improves overall and progression-free survival, and the proportion of patients achieving an overall objective response, compared with chemotherapy alone. In this study, we aimed to analyse patient-reported outcomes in GOG 240. Methods: Eligible adult participants (aged ≥18 years) had primary stage IVB or recurrent or persistent carcinoma of the cervix with measurable disease and GOG performance status of 0-1. Participants were randomly assigned by web-based permuted block randomisation (block size 4) in a 1:1:1:1 ratio to the four treatment groups: cisplatin (50 mg/m2 intravenously on day 1 or 2 of the treatment cycle) and paclitaxel (135 mg/m2 intravenously over 24 h or 175 mg/m2 intravenously over 3 h on day 1), with or without bevacizumab (15 mg/kg intravenously on day 1 or 2), or paclitaxel (175 mg/m2 over 3 h on day 1) and topotecan (0·75 mg/m2 for 30 min on days 1-3) with or without bevacizumab (15 mg/kg intravenously on day 1). Treatment assignment was concealed at randomisation (everyone was masked to treatment assignment, achieved by the use of a computer encrypted numbering system at the National Cancer Institute) and became open-label when each patient was registered to the trial. Treatment cycles were repeated every 21 days until disease progression or unacceptable toxicity, whichever occurred first. The coprimary endpoints of the trial were overall survival and safety; the primary quality-of-life endpoint was the score on the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI). For our analysis of patient-reported outcomes, participants were assessed before treatment cycles 1, 2, and 5, and at 6 and 9 months after the start of cycle 1, with the FACT-Cx TOI, items from the FACT-GOG-Neurotoxicity subscale, and a worst pain item from the Brief Pain Inventory. All patients who completed baseline quality-of-life assessments and at least one further follow-up assessment were evaluable for quality-of-life outcomes. This study is registered with ClinicalTrials.gov, number NCT00803062. Findings: Between April 6, 2009, and Jan 3, 2012, a total of 452 patients were enrolled in the trial, of whom 390 completed baseline quality-of-life assessment and at least one further assessment and were therefore evaluable for quality-of-life outcomes. In these patients, patient-reported outcome completion declined from 426 (94%) of 452 (at baseline) to 193 (63%) of 307 (9 months post-cycle 1), but completion rates did not differ significantly between treatment regimens (p=0·78). The baseline FACT-Cx TOI scores did not differ significantly between patients who received bevacizumab versus those who did not (p=0·27). Compared with patients who received chemotherapy alone, patients who received chemotherapy plus bevacizumab reported FACT-Cx TOI scores that were an average of 1·2 points lower (98·75% CI -4·1 to 1·7; p=0·30). Interpretation: Improvements in overall survival and progression-free survival attributed to the incorporation of bevacizumab into the treatment of advanced cervical cancer were not accompanied by any significant deterioration in health-related quality of life. Patients responding to anti-angiogenesis therapy who maintain an acceptable quality of life could be suitable at progression for treatment with other novel therapies that might confer additional benefit. Funding: National Institutes of Health.

Background: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. Findings: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p

Infection with the human papillomavirus (HPV) is the most common sexually transmitted disease afflicting approximately 80% of the population. HPV infection is an essential factor in cervical carcinogenesis and cervical carcinoma is the second most common cause of cancer among women worldwide. In addition to cervical cancer, other malignancies in both men and women such as esophageal, oropharyngeal, and anal cancer have been causally associated with this virus. Other gender-specific HPV-related cancers include penile, vulvar and vaginal cancer. HPV-16 is the most common HPV type associated with a malignant phenotype regardless of organ of origin. HPV-16 together with HPV-18 accounts for approximately 70% of cervical cancers. Other non-oncogenic HPV types including HPV types 6 and 11 are associated with over 90% of benign HPV-related lesions such as genital warts and juvenile respiratory papillomatosis. © 2007 Elsevier Inc. All rights reserved.

ObjectiveCurrently, we lack a theoretical explanation for why squamous cell cervical cancer develops predominantly in specific sites (i.e., along the squamocolumnar junction). We therefore implanted human cervical tissues containing the transformation zone in severe combined immunodeficiency (SCID) mice and studied morphology, steroid effects, gene expression, and human papillomavirus (HPV) factors.MethodsNormal and dysplastic human cervical tissues (3 x 2 mm) were placed subcutaneously in SCID-beige mice and later assessed by in situ hybridization for HPV 16/18 DNA and by immunohistochemistry for expression of CD31, keratin, proliferating-cell nuclear antigen, HPV 16 E6, p53, and Notch-1 (a binary cell fate determination protein). Some normal tissues were implanted with either a 90-day release 1.7-mg 17beta-estradiol pellet or a 5-mg tamoxifen pellet; others were infected prior to implantation with human recombinant adenovirus 5 vector containing a human cytomegalovirus promoter-driven beta-galactosidase gene and later assessed by X-gal staining.ResultsMurine and human vessels formed anastomoses by 3 weeks. For at least 11 weeks, normal tissue retained the transformation zone and normal cell-type-specific keratin expression and exhibited normal proliferation; Notch-1 was present only in the basal cell layer. Dysplastic tissues exhibited koilocytosis, increased levels of cellular proliferation, and aberrant keratin, p53, and Notch-1 expression; HPV 16/18 DNA and HPV 16 E6 protein were detected for at least 6 weeks. Squamous metaplasia of normal cervical epithelium resulted from estrogen exposure, and a predominant columnar differentiation pattern was associated with tamoxifen administration. Through stable adenovirus infection, beta-galactosidase was expressed for at least 6 weeks.ConclusionsThis small manipulatable xenograft model maintains normal and dysplastic human cervical epithelium through neovascularization. Neoplastic tissue retains HPV 16/18 DNA and a premalignant phenotype, including elevated levels of cellular proliferation and aberrant keratin, p53, and Notch-1 expression. These attributes constitute essential features of a biologic model through which one may study HPV-mediated human disease and may be superior to cell culture and transgenic murine systems. Furthermore, this may serve as a model for gene therapy. Finally, we suggest that the normal cervical epithelium is maintained through putative interactions between the Notch locus and cell cycle growth regulators such as p53 and pRb. Neoplastic cervical epithelium may arise through disruption of this pathway. This theory may be testable in our animal model.

ObjectiveOur purpose was to evaluate the role of interstitial brachytherapy in vulvar cancer management.Study designFrom 1985-1992 we performed a retrospective study of patients treated at the University of California, Irvine Medical Center, and Long Beach Memorial Medical Center.ResultsEleven patients received interstitial brachytherapy, with (n = 5) or without (n = 6) external beam radiotherapy, for locally advanced (n = 5) or recurrent (n = 6) vulvar cancer. Local control was achieved in all patients. Ten patients have died of disease at a mean interval of 33 months from the time of treatment, with 9 patients having maintenance of local control at death. One patient is alive without disease after 77 months of follow-up. There were 2 cases of local necrosis (18%) and 1 case of rectovaginal fistula (9%).ConclusionLocal control of advanced vulvar cancer can be achieved with interstitial brachytherapy, with or without external beam radiotherapy. With improved systemic therapy this treatment modality may be used to salvage women with bulky, symptomatic tumors.

ObjectiveOur goal was to use population-based data to determine the difference in 5-year survival in women diagnosed with cervical cancer between those aged 18-34 years and those aged 40-60 years.Study designThe SEER (Surveillance, Epidemiology, and End Results) public-use database, 1973-1994, was used for this investigation. Only subjects with cervical carcinoma diagnosed between 1988 and 1990 were included. Subjects were stratified on age at diagnosis (

ObjectiveTo perform a phase I study of topically applied dihematoporphyrin ether (DHE) in the photodynamic treatment (PDT) of cervical intraepithelial neoplasia (CIN) using fixed DHE doses and application schedules, and a variable dose of 630 nm red light delivered by an argon-pumped dye laser.MethodsBetween February 1993 and April 1994, 24 nonpregnant women with a histologic diagnosis of CIN were enrolled. All patients had lesions involving at least 25% of the cervix that were colposcopically visible. Using a cervical cap, 2 ml of a 1% solution of DHE (Photofrin) in a 4% Azone and isopropyl alcohol vehicle were applied to the cervix 24 hr prior to PDT. An argon-pumped dye laser providing light at 630 nm was then used to perform PDT. Light was coupled into a 400-microm silica fiber optic terminating in a microlens which focused the laser radiation onto a circular field of uniform light intensity perpendicular to the tissue. The entire ectocervix was treated in a single field including a margin of 3-5 mm of normal cervix. Using a constant power density (150 mW/cm2) to avoid thermal injury, the PDT energy was increased every 4 patients in a phase I fashion (40, 60, 80, 100, 120, and 140 J/cm2).ResultsThirteen patients with CIN I, 7 patients with CIN II, and 4 patients with CIN III were treated. The maximal energy density was well tolerated. Toxicity was minimal with no patients experiencing local necrosis, sloughing, or scarring; however, a mild vaginal discharge was noted in several patients. Systemic effects were absent. After 12 months of follow-up at 3-month intervals, 22 patients are evaluable of whom 15 (68%) are disease free. One patient was lost to follow-up and in another the cervical cap was dislodged. Four of the 7 failures or recurrences occurred at energy densities of 80 J/cm2 or less, while 8 of 11 (73%) patients were treated successfully with PDT at an energy density of 100 to 140 J/cm2.ConclusionsPDT with DHE and an argon-pumped dye laser at 630-nm wavelength delivering an energy density of 140 J/cm2 is safe and effective in treating CIN. Phase II studies using PDT at the prescribed application schedule and dose are indicated.

Patients who develop locally recurrent uterine corpus or uterine cervix cancer after primary surgery are usually treated with radiotherapy. The optimal radiotherapeutic approach, however, has not been defined. We report the use of exploratory laparotomy, omental pedicle grafting, and intraoperative transperineal interstitial brachytherapy in the treatment of 28 such patients (10 with recurrent corpus and 18 with recurrent cervix cancer). In addition, 22 patients also received perioperative whole pelvic teletherapy while 21 also received a second closed interstitial application. Local control was achieved in 20 patients (71%), but only 10 (36%) continue to be alive without disease after a median of 44 months. Eighteen patients have died (17 of disease) a median of 13 months after open implant. Patients treated with a single implant (n = 7), with side wall involvement (n = 5), with tumors greater than 6 cm in size (n = 4), with a history of previous pelvic irradiation (n = 8), or with persistent disease after open interstitial therapy (n = 8), were not salvaged. Ten patients suffered acute morbidity which included deep venous thrombosis (n = 1), wound separation (n = 1), urinary infection (n = 2), wound infection (n = 2), pneumonia (n = 1), and fever (n = 3). Two other patients experienced chronic non-tumor-related comorbidities. These included a vesicovaginal fistula with a rectovaginal fistula in 1 patient and a small bowel obstruction with a ureteral stricture in another. A single individual suffered from both acute and chronic complications (fever, ureterointestinal fistula).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: The purpose of this study was to demonstrate a methodology for auditing the impact of HCII testing on the direct cost of cervical cancer cytological screening, where the test is collected in all women screened and processed routinely in women age 30 years and older. MATERIALS AND METHODS: After a policy change to screen all patients 30 years or older with both Pap smears and high-risk human papillomavirus (HR-HPV), as well as cocollection of HR-HPV in women younger than 30 years, all cytological, HPV, and histological data pertaining to cervical screening was collected retrospectively during a 2-month period. We documented the direct costs of performing these tests and estimated the necessary compliance rate for balanced cost-effectiveness. RESULTS: During the 2-month period, 8,300 women were screened with both Pap smear and HPV cocollection. Of the 'nonnormal' cytological findings, 5% of patients showed either atypical squamous cells (3.5%) or squamous intraepithelial abnormalities (1.5%). An additional 427 (5%) patients had the finding of positive HR-HPV with normal cytology. Six of these patients opted for immediate colposcopy, 2 of which were found to have cervical intraepithelial neoplasia 2. In women age 30 years and older, 900 patients per 1,000 screened would be eligible for a 2-year screening interval based on negative cytology and negative HR-HPV. Based on the direct costs associated with this cohort, no more than 164 women could request screening at an interval shorter than 3 years for the total costs of such a program to equal that of one without HR-HPV cocollection. CONCLUSIONS: By adding HCII collection to the Pap smear for our entire screening cohort, we intended to reduce the number of tests performed, which was impacted by its age distribution. Our findings indicate that at least 736 of the 900 double-negative patients (82%) would have to be screened at no less than 3 years for such a screening paradigm to be cost-effective in managing women 30 years and older. [ABSTRACT FROM AUTHOR]

Objective. To determine the cumulative risk of cervical intraepithelial neoplasia (CIN) 2 or 3 in patients with atypical squamous cells, cannot exclude HSIL (ASC-H).Methods. A retrospective analysis was performed to identify patients referred to the dysplasia clinic with ASC-H. Initial evaluation included colposcopy, endocervical curettage, and an ectocervical biopsy, when indicated, in all the patients. A follow-up evaluation was performed at 6 and 12 months. Cumulative histological diagnosis of CIN 2 or 3 at 12 months served as the clinical end point.Results. Two hundred twenty-nine patients with ASC-H and with a mean age of 32.8 years were evaluated. At the time of initial colposcopy, only 10.0% (23/229; 95% CI = 6.5%-15%) of the patients had histological evidence of CIN 2 or 3. The cumulative risk of CIN 2 or 3 was 12.2% (95% CI = 8%-17%).Conclusions. Evaluation of patients with ASC-H with colposcopy does lead to the detection of CIN 2 or 3 but perhaps at a rate lower than previously reported. [ABSTRACT FROM AUTHOR]

Context: Women diagnosed with ovarian cancer are at risk for reduced quality of life (QOL). It is imperative to further define these declines to interpret treatment outcomes and design appropriate clinical interventions.Objectives: The primary objective of this study was to compare data obtained from ovarian cancer patients with normative data to assess the degree to which QOL differs from the norm. Secondary objectives were to examine demographic variables and determine if there was a correlation between physical/functional and social/emotional scores during chemotherapy.Methods: Patients with Stage III/IV ovarian cancer on Gynecologic Oncology Group Protocols 152 and 172 who underwent surgery followed by intravenous paclitaxel and cisplatin completed the Functional Assessment of Cancer Therapy-Ovarian. The Functional Assessment of Cancer Therapy scale includes the four domains of physical, functional, social, and emotional well-being (PWB, FWB, SWB, and EWB, respectively).Results: Ovarian cancer patients had a total QOL (Functional Assessment of Cancer Therapy-General) score similar to the U.S. female adult population. However, the reported subscale scores were 2.0 points (95% confidence interval [CI] 1.4-2.5, P<0.001, effect size=0.37) lower in PWB, 0.9 points (95% CI 0.3-1.5, P=0.005, effect size=0.13) lower in FWB, 5.0 points (95% CI 4.6-5.3, P<0.001, effect size=0.74) higher in SWB, and 0.8 points (95% CI 0.3-1.2, P<0.001, effect size=0.16) lower in EWB. Correlation between the sum of PWB and FWB and the sum of SWB and EWB was r=0.53 (P<0.001). Age was positively correlated with EWB (r=0.193; 95% CI 0.09-0.29).Conclusion: Ovarian cancer patients have decreased QOL in physical, functional, and emotional domains; however, they may compensate with increased social support. At the time of diagnosis and treatment, patients' QOL is affected by inherent characteristics. Assessment of treatment outcomes should take into account the effect of these independent variables. [ABSTRACT FROM AUTHOR]