[Show abstract][Hide abstract] ABSTRACT: Purpose:
To describe estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels during the first year of monthly triptorelin plus exemestane or tamoxifen and to assess possible suboptimal suppression while receiving exemestane plus triptorelin.
Patients and methods:
Premenopausal patients with early breast cancer on the Suppression of Ovarian Function Trial who selected triptorelin as the ovarian suppression method and were randomly assigned to exemestane plus triptorelin or tamoxifen plus triptorelin were enrolled until the target population of 120 patients was reached. Blood sampling time points were 0, 3, 6, 12, 18, 24, 36, and 48 months. Serum estrogens were measured with a highly sensitive and specific assay. This preplanned 12-month analysis evaluated E2, E1, E1S, follicle-stimulating hormone, and luteinizing hormone levels in all patients and the proportion of patients with E2 levels greater than 2.72 pg/mL at any time point during treatment with exemestane plus triptorelin.
One hundred sixteen patients (exemestane, n = 86; tamoxifen, n = 30; median age, 44 years; median E2, 51 pg/mL; 55% prior chemotherapy) started triptorelin and had one or more samples drawn. With exemestane plus triptorelin, median reductions from baseline E2, E1, and E1S levels were consistently ≥ 95%, resulting in significantly lower levels than with tamoxifen plus triptorelin at all time points. Among patients on exemestane plus triptorelin, 25%, 24%, and 17% had an E2 level greater than 2.72 pg/mL at 3, 6, and 12 months, respectively. Baseline factors related to on-treatment E2 level greater than 2.72 pg/mL were no prior chemotherapy (P = .06), higher body mass index (P = .05), and lower follicle-stimulating hormone and luteinizing hormone (each P < .01).
During the first year, most patients on exemestane plus triptorelin had E2 levels below the defined threshold of 2.72 pg/mL, consistent with levels reported in postmenopausal patients on aromatase inhibitors, but at each time point, at least 17% of patients had levels greater than the threshold.
Preview · Article · Jan 2016 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: More than 429,000 patients worldwide are diagnosed with bladder cancer each year and muscle-invasive bladder cancer has an especially poor outcome. The median age at diagnosis is over 70 years, and many patients also have a substantial number of age-associated impairments that need to be considered when planning therapeutic interventions.
Here, we report the case of a 63-year-old man with a cT3b urothelial carcinoma which was surgically removed. No neoadjuvant or adjuvant chemotherapy was administered. After 18 months a lung metastasis was confirmed and resected but no chemotherapy was given after surgery. Twelve months later, the patient relapsed and was treated with a combination of gemcitabine and cisplatin and after a decline in renal function the treatment was changed to a combination of carboplatin and gemcitabine which resulted in a partial response which lasted 8 months. Following this vinflunine was administered as a second line treatment. Here we review the evidence available in the literature regarding the suitability of different treatment options for managing muscle-invasive bladder cancer at each step of the case presentation.
Bladder cancer treatment requires a multidisciplinary approach. Although, depending on the clinical characteristics of the patient, there are some controversial points in the management of this pathology we hope that the scientific data and the clinical trials reviewed in this case report, can help to guide physicians to make more rational decisions regarding the management of these patients.
[Show abstract][Hide abstract] ABSTRACT: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been revolutionized in recent years. It is well known that androgen receptor is still active in most patients with disease progression and serum testosterone levels <50ng/dL. Moreover, further hormonal maneuvers, either through decreasing androgen levels (abiraterone) or by targeting the androgen receptor (AR) pathway (enzalutamide), prolong survival. In addition, a new cytostatic able to overcome docetaxel resistance, cabazitaxel, and the radioisotope radium 223 have been incorporated to the armamentarium of mCRPC. mCRPC is not only a heterogeneous tumor, it changes over time developing neuroendocrine features or selection of clones resistant to hormonal maneuvers. In addition, the multiplicity of current treatments, make it necessary to design algorithms that help the specialist to choose the most appropriate treatment for a particular patient. The lack of randomized trials comparing face to face the different available options limit the scope of this review. In this article, the authors describe the prognostic factors for first line therapy in patients with mCRPC, and propose a treatment algorithm for mCRPC based on the levels of scientific evidence available and, if not available, on the consensus between medical professionals. Finally, the panel discuss how to define progressive disease in the setting of mCRPC and treatment with targeted therapies.
No preview · Article · Sep 2015 · Critical reviews in oncology/hematology
[Show abstract][Hide abstract] ABSTRACT: This review provides updated information published in 2014 regarding advances and major achievements in genitourinary cancer. Sections include the best in prostate cancer, renal cancer, bladder cancer, and germ cell tumors. In the field of prostate cancer, data related to treatment approach of hormone-sensitive disease, castrate-resistant prostate cancer, mechanisms of resistance, new drugs, and molecular research are presented. In relation to renal cancer, relevant aspects in the treatment of advanced renal cell carcinoma, immunotherapy, and molecular research, including angiogenesis and von Hippel-Lindau gene, molecular biology of non-clear cell histologies, and epigenetics of clear renal cell cancer are described. New strategies in the management of muscle-invasive localized bladder cancer and metastatic disease are reported as well as salient findings of biomolecular research in urothelial cancer. Some approaches intended to improve outcomes in poor prognosis patients with metastatic germ cell cancer are also reported. Results of clinical trials in these areas are discussed.
No preview · Article · Jul 2015 · CANCER AND METASTASIS REVIEW
[Show abstract][Hide abstract] ABSTRACT: Androgen deprivation treatment is the current standard first-line treatment for metastatic prostate cancer. For several years, docetaxel was the only treatment with a proven survival benefit for castration-resistant prostate cancer (CRPC). Since docetaxel became standard of care for men with symptomatic metastatic castration-resistant prostate cancer (CRPC), three treatment virtual spaces, for treatment and drug development in CPRC, have emerged: pre-docetaxel, docetaxel combinations and post-docetaxel. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 have been approved in the pre- or post-docetaxel setting in metastatic CRPC during the last few years. Patients are now living longer and experiencing better quality of life. Strategies for patient selection and treatment sequencing are therefore urgently required.
Full-text · Article · Oct 2014 · Clinical and Translational Oncology
[Show abstract][Hide abstract] ABSTRACT: Background:
Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR.
Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla.
Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5-75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a ≥ 10 % decrease in the left ventricular ejection fraction.
The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.
No preview · Article · Jul 2014 · International Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Background
Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programmes (EAPs) were established worldwide, allowing access to cabazitaxel before its commercial availability. Preliminary results of the European CUP/EAP, focusing on the elderly population (aged ⩾70 years), are reported.
Patients and methods
Enrolled patients with progressive mCRPC received cabazitaxel (25 mg/m2) plus 10 mg oral prednisone/prednisolone every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. Safety was analysed by age group (<70, [70–75] and ⩾75 years). The influence of selected variables on grade ⩾3 neutropenia and/or neutropenic complications was analysed in multivariate analysis.
746 men were enrolled (<70 years, n = 421; [70–75], n = 180, ⩾75 years, n = 145). Number of cabazitaxel cycles, dose reductions for any cause, dose delays possibly related to cabazitaxel adverse events, and tolerability were similar in the three age groups. Prophylactic granulocyte colony-stimulating factor (G-CSF) use was more common in men aged ⩾70 years. In multivariate analysis, age ⩾75 years, treatment cycle 1, and neutrophil count <4000/mm3 before cabazitaxel injection were associated with increased risk of developing grade ⩾3 neutropenia and/or neutropenic complications. Prophylactic use of G-CSF at a given cycle significantly reduced this risk by 30% (odds ratio 0.70, p = 0.04).
The results suggest that cabazitaxel has a manageable safety profile in everyday clinical practice. Prophylactic use of G-CSF, especially at cycle 1 and in men aged ⩾75 years, is important and improves tolerability in senior adults treated with cabazitaxel.
No preview · Article · Apr 2014 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Among the many papers were presented at the 36th San Antonio Breast Cancer Symposium in 2013; the most important −mainly oral presentations−are summarized below. Notable for their clinical applicability were two studies on the management of the primary tumor in metastatic breast cancer and the PRIME II trial evaluating the impact of omitting adjuvant radiotherapy in elderly patients. The expected data from the BETH trial, evaluating the benefit of adding bevacizumab in the adjuvant treatment of HER2-positive tumors, were also reported, and interesting information was presented on the efficacy of carboplatin in triple-negative breast cancer. From the point of view of tumor biology, the organizers wanted to provide a platform for the potential role of immunity in the prognosis of breast cancer, and mutations in the estrogen receptor gene, which are emerging as a new mechanism of acquisition of hormone resistance.
[Show abstract][Hide abstract] ABSTRACT: In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy.
We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495.
Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5·4 years (IQR 3·1-6·8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48-66) in patients in the trastuzumab group and 43% (34-52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0·64 (95% CI 0·44-0·93; two-sided log-rank p=0·016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0·29 (95% CI 0·11-0·78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group).
These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.
F Hoffmann-La Roche.
Full-text · Article · Mar 2014 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance.
We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.
TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.
We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
[Show abstract][Hide abstract] ABSTRACT: Background:
Levels of bone turnover markers (BTM) might be correlated with outcome in terms of skeletal-related events (SRE), disease progression, and death in patients with bladder cancer (BC) and renal cell carcinoma (RCC) with bone metastases (BM). We try to evaluate this possible correlation in patients who receive treatment with zoledronic acid (ZOL).
This observational, prospective, and multicenter study analysed BTM and clinical outcome in these patients. Serum levels of bone alkaline phosphatase (BALP), procollagen type I amino-terminal propeptide (PINP), and beta-isomer of carboxy-terminal telopeptide of type I collagen (β-CTX) were analysed.
Patients with RCC who died or progressed had higher baseline β-CTX levels and those who experienced SRE during follow-up showed high baseline BALP levels. In BC, a poor rate of survival was related with high baseline β-CTX and BALP levels, and new SRE with increased PINP levels. Cox univariate analysis showed that β-CTX levels were associated with higher mortality and disease progression in RCC and higher mortality in BC. Bone alkaline phosphatase was associated with increased risk of premature SRE appearance in RCC and death in BC.
Beta-isomer of carboxy-terminal telopeptide of type I collagen and BALP can be considered a complementary tool for prediction of clinical outcomes in patients with BC and RCC with BM treated with ZOL.
Full-text · Article · Jun 2013 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC).
The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib.
High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023).
We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.
No preview · Article · Jun 2013 · Annals of Oncology
[Show abstract][Hide abstract] ABSTRACT: PURPOSEEpidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. PATIENTS AND METHODS
Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of α = .10 with no adjustments for multiplicity.ResultsThe full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue. CONCLUSION
While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC.
Full-text · Article · Jun 2013 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Bone metastases are a common complication of advanced prostate cancer and while they are less common in non-prostate genitourinary (GU) malignances, they have been reported in up to 35 % of patients with advanced renal cell carcinoma and bladder cancer. Furthermore, they may occur in more than two-thirds of those patients with bladder cancer who develop distant metastases. In the absence of bone-targeted therapies, approximately 50 % of all patients with metastatic bone disease from GU cancers experience at least one skeletal-related event within their lifetime. Zoledronic acid is a bisphosphonate that has been shown to delay or prevent the development of skeletal complications in patients with bone metastases and reduce bone pain in these patients. Furthermore, zoledronic acid has also demonstrated the ability to prevent osteopenia, which may occur with the prolonged use of some pharmacological interventions in patients with cancer.
No preview · Article · Apr 2013 · Clinical and Translational Oncology
[Show abstract][Hide abstract] ABSTRACT: Context: Controversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus. Objective: To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety. Evidence Acquisition: Two meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease. Evidence Synthesis: This document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG). Conclusions: With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC. (c) 2012 AEU. Published by Elsevier Espana, S.L. All rights reserved.
No preview · Article · Dec 2012 · Actas urologicas españolas
[Show abstract][Hide abstract] ABSTRACT: ContextControversies and uncertainties among integral management of advanced castration resistant prostate cancer continue to exist despite the number of evidence based clinical practice guidelines published with high international consensus.Objective
To develop a document that reviews the management of controversies in advanced castration resistant prostate cancer, with recommendations from the definition, to the management in hormonal maneuvers, first-line treatment and second-line with new treatments as cabazitaxel or abirarerone and the multidisciplinary approach of the pathology with the goal of finding the most efficient, best time to act and safety.Evidence AcquisitionTwo meetings of a multidisciplinary group of experts involved in the management of this disease (Oncologist and Urologist) where pooled analysis of original literature and reached consensus document of recommendations on castration resistant prostate cancer, reviewing and attempting to address the current controversies of the disease.Evidence SynthesisThis document is endorsed by the corresponding Scientific Associations and Working Groups involved in the current management of Genitourinary Tumours: the Spanish Association of Urology (AEU) with the Uro-Oncoloy Group (GUO) and the Spanish Oncology of Genitourinary Group (SOGUG).Conclusions
With the adaptation and implementation of this Document of Recommendations for clinical practice are available for the first time, a real road map for quality, efficiency and safety in the management of patients with CRPC.
No preview · Article · Nov 2012 · Actas urologicas españolas
[Show abstract][Hide abstract] ABSTRACT: Background
Aromatase inhibitors (AIs) may promote ovarian function recovery (OFR). True incidence, predictors and impact on the outcome of OFR are unknown.Patients and methodsWe carried out a prospective study to assess ovarian function in estrogen receptor (ER)-positive BC patients on tamoxifen who had at least 2 years of chemotherapy-induced amenorrhea (CIA) and postmenopausal E2 levels. Patients switched to exemestane and underwent a series of investigations including vaginal ultrasound, antimullerian hormone, follicle stimulating hormone (FSH), and E2. E2 measurements were made using a clinical assay (direct) and a highly sensitive (indirect) immunoassay for comparison.ResultsBoth E2 assays (indirect versus direct) showed a similar incidence of OFR 32% (95% CI 19.5-44.5) versus 30% (95% CI 17.7-42.3) and median time to OFR 5.4 months (95% CI 1.2-9.6) versus 6.0 months (95% CI 4.8-7.1).On multivariate analysis, the mean age at the start of exemestane treatment was the only marker associated with probability of OFR (OR: 0.44, 0.24-0.78; P = 0.006). According to a receiver operating characteristic (ROC) analysis, age <48 years predicted for OFR (sensitivity: 59%; 1-specificity: 17%; AUC: 0.796; P = 0.001). Patients with OFR had higher mean E2 levels (43.6 versus 5.76 pmol/l; P = 0.001) and a reduced disease-free survival [DFS; HR 9.3 (95% CI 3.3-48.0; P = 0.04)] than those without it.Conclusion
Even with a clinical and biochemical profile compatible with menopause, switching from tamoxifen to an AI should be avoided in patients <48 with CIA.
Full-text · Article · Oct 2012 · Annals of Oncology