The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics, despite prolific drug development. ...Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free survival and overall survival, although the cure rates have been affected only modestly. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, growth in our armamentarium offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial 'ovarian' cancer and describes the direction and early results of clinical investigation.
We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary ...peritoneal carcinoma.
A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration
time curve 6) and paclitaxel (175 mg/m
) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for
and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.
Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8
32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for
mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-
HRR, the HR was 0.65 (95% CI, 0.51 to 0.85).
, HRR, and CD31 were not predictive of bevacizumab activity.
No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for
mutations and homologous recombination deficiency is essential.
To examine the use of inpatient hysterectomy and explore changes in the use of various routes of hysterectomy and patterns of referral.
The Nationwide Inpatient Sample was used to identify all women ...aged 18 years or older who underwent inpatient hysterectomy between 1998 and 2010. Weighted estimates of national trends were calculated and the number of procedures performed estimated. Trends in hospital volume and across hospital characteristics were examined.
After weighting, we identified a total 7,438,452 women who underwent inpatient hysterectomy between 1998 and 2010. The number of hysterectomies performed annually rose from 543,812 in 1998 to a peak of 681,234 in 2002; it then declined consistently annually and reached 433,621 cases in 2010. Overall, 247,973 (36.4%) fewer hysterectomies were performed in 2010 compared with 2002. From 2002 to 2010 the number of hysterectomies performed for each of the following indications declined: leiomyoma (-47.6%), abnormal bleeding (-28.9%), benign ovarian mass (-63.1%), endometriosis (-65.3%), and pelvic organ prolapse (-39.4%). The median hospital case volume decreased from 83 procedures per year in 2002 to 50 cases per year in 2010 (P<.001).
The number of inpatient hysterectomies performed in the United States has declined substantially over the past decade. The median number of hysterectomies per hospital has declined likewise by more than 40%.
III.
Summary Background Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore ...the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. Methods The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel 175 mg/m2 of body surface area and carboplatin area under the curve 5) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00565851. Findings Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5–62·2 for chemotherapy plus bevacizumab; IQR 40·8–59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7–46·2) versus 37·3 months (32·6–39·7) in the chemotherapy group (hazard ratio HR 0·829; 95% CI 0·683–1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680–0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 12% vs two 1%), fatigue (27 8% vs eight 2%), and proteinuria (27 8% vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection n=1 and myelodysplastic syndrome n=1) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection n=1, febrile neutropenia n=1, myelodysplastic syndrome n=1, secondary malignancy n=1; deaths not classified with CTCAE terms: disease progression n=3, sudden death n=1, and not specified n=1). Interpretation The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. Funding National Cancer Institute and Genentech.
Opportunistic salpingectomy at the time of hysterectomy or as an alternative to bilateral tubal ligation may reduce the incidence of ovarian cancer, because it has been demonstrated that most serous ...ovarian cancers begin in the fallopian tubes. However, salpingectomy at the time of sterilization is not always financially covered by third-party payers, and this represents a barrier to adoption. Routine salpingectomy has become more common but is not always practiced at the time of hysterectomy.
This study aimed to determine the impact of opportunistic salpingectomy as an alternative tubal ligation and routine salpingectomy at the time of hysterectomy on ovarian cancer mortality and overall cost.
An 8-state Markov state transition model was constructed, including hysterectomy, tubal ligation, and ovarian cancer. Transition probabilities were informed by previously reported population data and include age-adjusted rates of elective sterilization and hysterectomy. This model was used to predict ovarian cancer incidence and the cost effectiveness of opportunistic salpingectomy. Testing of this model suggested that it accurately predicted overall life expectancy and closely predicted the rate of hysterectomy in the population. The model may underestimate the rate of tubal sterilization, making it conservative with respect to the benefits of salpingectomy.
The recursive Markov model was run from ages 20 to 85 years in 1-year intervals with a half step correction and included age-adjusted rates of tubal ligation, hysterectomy (with and without oophorectomy), and ovarian cancer. The model predicts that opportunistic salpingectomy at the time of tubal ligation will reduce ovarian cancer mortality by 8.13%. Opportunistic salpingectomy at the time of hysterectomy will reduce ovarian cancer mortality by 6.34% for a combined decrease of 14.5%. Both strategies are cost effective when considering only the cost of the opportunistic salpingectomy. The excess cost of opportunistic salpingectomy at the time of tubal ligation was $433.91 with an incremental cost-effective ratio of $6401 per life-year and $5469 per quality-adjusted life year gained when adjusting for ovarian cancer with a utility of 0.64. The incremental cost-effective ratio for opportunistic salpingectomy during hysterectomy at a cost of $124.70 was $2006 per life-year and $1667 per quality-adjusted life year. When considering the impact of ovarian cancer prevention with respect to the cost of ovarian cancer treatment, opportunistic salpingectomy may produce a substantial healthcare savings. Utilizing a 3% discount rate, it is estimated that the total savings for universal salpingectomy could be as high as $445 million annually in the United States. A sensitivity analysis around the benefit of opportunistic salpingectomy suggests that this procedure will be cost effective even if salpingectomy provides only a modest reduction in the risk of ovarian cancer.
It is estimated that universal opportunistic salpingectomy may prevent 1854 deaths per year from ovarian cancer and may reduce healthcare costs. Given these data, universal opportunistic salpingectomy should be considered at the time of tubal ligation and hysterectomy and covered by third-party payers.
A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% ...with placebo.
Contemporary management of endometrial cancer Wright, Jason D, MD; Medel, Nicanor I Barrena, MD; Sehouli, Jalid, MD ...
The Lancet (British edition),
04/2012, Letnik:
379, Številka:
9823
Journal Article
Recenzirano
The treatment of endometrial cancer has changed substantially in the past decade with the introduction of a new staging system and surgical approaches accompanied by novel adjuvant therapies. Primary ...surgical treatment is the mainstay of therapy but the effectiveness and extent of lymphadenectomy has been challenged, and its acceptance as a routine procedure varies by country. The role of radiation has evolved and chemotherapy has been incorporated, either alone or combined with radiation, to treat the many patients in whom cancer recurs because of a tumour outside the originally radiated pelvic and lower abdominal area. Use of traditional adjuvant chemotherapeutics has been challenged in clinical trials of new agents with improved side-effect profiles. Novel agents and targeted therapies are being investigated. Research into genetic susceptibility to endometrial cancer and the potential genetic aberrations that might translate into therapeutic interventions continues to increase. Substantial global variability in the treatment of endometrial cancer has led to examination of long-accepted norms, which has resulted in rapidly changing standards. International cooperation in clinical trials will hasten progress in treatment of this ubiquitous cancer.
Pazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical ...studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy.
Nine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators.
Maintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio HR, 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%).
Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).
Summary 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<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 54% of 452 patients in the placebo group vs 258 56% of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 17% patients vs 27 6%, respectively) and higher incidences of oedema (294 64% patients had any-grade oedema in the trebananib group vs 127 28% patients in the placebo group). Grade 3 or higher adverse events included ascites (34 8% in the placebo group vs 52 11% in the trebananib group), neutropenia (40 9% vs 26 6%), and abdominal pain (21 5% vs 22 5%). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 17% vs 46 10%). Interpretation Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Funding Amgen.
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