Hopes and failures in front-line ovarian cancer therapy Tsibulak, Irina; Zeimet, Alain G.; Marth, Christian
Critical reviews in oncology/hematology,
November 2019, 2019-Nov, 2019-11-00, 20191101, Volume:
143
Journal Article
Peer reviewed
Open access
Display omitted
Through the last three decades, the combination of paclitaxel and carboplatin remains the standard of care chemotherapy in newly diagnosed epithelial ovarian cancer (EOC). Based on a ...single trial, first-line maintenance therapy with angiogenesis inhibitor bevacizumab was approved in Europe and widely applied. In 2018, based on a second trial bevacizumab was approved for first-line maintenance in the United States. Despite complete remission upon chemotherapy, the majority of the patients recur. A large number of randomized trials were conducted to explore the optimal front-line therapy regimen, but neither dose-densing, nor adding of a third chemotherapy agent or intraperitoneal administration could improve overall survival (OS). Also implementation of hyperthermic intraperitoneal chemotherapy (HIPEC) or the neoadjuvant approach failed to improve OS.
Recently, maintenance therapy with PARP inhibitors showed encouraging results in patients with BRCA1/2 mutation. Further trials with targeted therapies are ongoing.
Here we review the achievements of front-line therapy in primary advanced EOC through the last three decades and discuss future treatment strategies.
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on ...endometrial cancer was held on 11-13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically-relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.
Summary Background Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as ...bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. Methods In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov , number NCT00556374. Findings Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio HR 0·50 95% CI 0·39–0·65, p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of −1 or higher at baseline (n=1872, HR 0·44 95% CI 0·31–0·64, p<0·0001) and in those with a bone mineral density T-score of less than −1 already at baseline (n=1548, HR 0·57 95% CI 0·40–0·82, p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 30% in each group). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. Interpretation Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. Funding Amgen.
Folate can be transported into the cell by the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), or the folate receptor (FR), of which various isoforms exist. While the RFC ...and PCFT are expressed by many normal cells, the FR is present only in a small proportion of normal tissues. In these tissues, the FR expression level is often low and restricted to the apical surface of polarized epithelial cells. In contrast, FR is expressed on the blood-accessible basal and lateral membranes of many types of epithelial cancer. Considering that FR is expressed in few nonmalignant cell types on luminal membranes generally not accessible for molecules transported in the blood, FR is considered a promising antitumor target. As FR expression seems associated with tumor progression and prognosis, anticancer therapies targeting FR are currently being developed, such as farletuzumab (Morphotek, Exton, PA, USA), IMGN853 (ImmunoGen, Waltham, MA, USA), vintafolide, and EC1456 (both Endocyte Inc., West Lafayette, IN, USA). FR expression could be used as a response-predictive biomarker for these treatments. The ability to identify patients and treat them with an effective therapy based on the known expression of the tumor marker would, indeed, be the next step in predictive medicine for these patients. This review summarizes the role of FR in ovarian cancer and the value of FR as a prognostic biomarker for ovarian cancer and a response-predictive biomarker for folate-targeted therapeutics.
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).
To determine current practice patterns with regard to gynecologic high-dose-rate (HDR) brachytherapy among international members of the Gynecologic Cancer Intergroup (GCIG) in Japan/Korea (Asia), ...Australia/New Zealand (ANZ), Europe (E), and North America (NAm).
A 32-item survey was developed requesting information on brachytherapy practice patterns and standard management for Stage IB-IVA cervical cancer. The chair of each GCIG member cooperative group selected radiation oncology members to receive the survey.
A total of 72 responses were analyzed; 61 respondents (85%) used HDR. The three most common HDR brachytherapy fractionation regimens for Stage IB-IIA patients were 6 Gy for five fractions (18%), 6 Gy for four fractions (15%), and 7 Gy for three fractions (11%); for Stage IIB-IVA patients they were 6 Gy for five fractions (19%), 7 Gy for four fractions (8%), and 7 Gy for three fractions (8%). Overall, the mean combined external-beam and brachytherapy equivalent dose (EQD2) was 81.1 (standard deviation SD 10.16). The mean EQD2 recommended for Stage IB-IIA patients was 78.9 Gy (SD 10.7) and for Stage IIB-IVA was 83.3 Gy (SD 11.2) (p = 0.02). By region, the mean combined EQD2 was as follows: Asia, 71.2 Gy (SD 12.65); ANZ, 81.18 (SD 4.96); E, 83.24 (SD 10.75); and NAm, 81.66 (SD, 6.05; p = 0.02 for Asia vs. other regions).The ratio of brachytherapy to total prescribed dose was significantly higher for Japan (p = 0.0002).
Although fractionation patterns may vary, the overall mean doses administered for cervical cancer are similar in Australia/New Zealand, Europe, and North America, with practitioners in Japan administering a significantly lower external-beam dose but higher brachytherapy dose to the cervix. Given common goals, standardization should be possible in future clinical trials.
Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of ...aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial.
ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition.
Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio HR, 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen.
BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin.
2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer. This report provides the outcomes from the Fourth Ovarian Cancer Consensus Conference.
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.
Purpose
The aim of the present study was to assess the impact of postponed screening examinations and lockdown measures on gynecological and breast cancer diagnoses throughout the year 2020 in a ...gynecological oncological center in Austria.
Methods
Data of 889 patients with either newly diagnosed gynecological or breast cancer between January 2019 and December 2020 were collected. Clinical parameters including symptoms, performance status, comorbidities and referral status were compared in patients, who were newly diagnosed with cancer in the period of the first lockdown from March 2020 to April 2020 and the second lockdown from November 2020 to December 2020 and compared to the same period in 2019.
Results
Our results showed a strong decline in newly diagnosed cancers during the lockdown periods: −45% in gynecological cancer and -52% in breast cancer compared to the same period in 2019. Compared to the analogue period of 2019, breast cancer patients reported significantly more tumor-associated symptoms (55% vs. 31%,
p
= 0.013) during and in between (48% vs. 32%,
p
= 0.022) the lockdowns. During the lockdown, periods in the group of breast cancer patients’ tumor stage varied significantly compared to 2019 (T2–T4;
p
= 0.047).
Conclusion
Both lockdowns led to a strong decrease in newly diagnosed gynecological and breast cancers. Treatment delays in potentially curable disease could lead to inferior clinical outcomes, with the risk of missing the optimal treatment window. As the COVID-19 pandemic will be a challenge for some time to come, new strategies in patient care are needed to optimize cancer screening and management during the pandemic.
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