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Prostate cancer is the most common cancer in men, with an incidence that is expected to increase in the coming years. Prostate cancer is usually diagnosed in men >65 years of age, thus the concurrent presence of cardiovascular diseases might influence the treatment, owing to the increased risk of cardiovascular mortality. The introduction of new drugs, such as abiraterone and enzalutamide for the management of metastatic disease has created further interest in treatment-related cardiovascular toxicities, although limited data from trials specifically designed to identify cardiovascular toxicities of these agents are currently available. The only available data are derived from published phase II-III study reports, expanded access or compassionate use programmes and meta-analyses of the effects of systemic therapies that are already approved for use in clinical practice or are in the early phases of development. These data are conflicting, although they seem to suggest that certain drugs are associated with an increased risk of cardiovascular adverse events. Clinical trial methodology could be improved by the enrolment of greater numbers of patients >65 years of age, and the use of comprehensive cardiological evaluations. Moreover, closer collaboration between oncologists and cardiologists is essential for the identification and/or management of cardiovascular adverse events in patients with prostate cancer.

Aim: High rate of non-target lesions in metastatic castration-resistant prostate cancer usually limits applicability of Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and this has led to a growing interest in using PET/computed tomography (CT). We prospectively investigated the role of 18F-choline (FCH)-PET/CT in patients receiving enzalutamide after docetaxel. Patients & methods: 30 patients were monitored by means of FCH-PET/CT before and during the treatment. A Cox proportional hazards regression model was used to assess the associations between metabolic parameters and clinical outcomes. Results: Univariate analysis showed no significant correlation between biochemical and FCH-PET responses. Multivariate analysis showed that only baseline maximum standardized uptake value (SUVmax) significantly correlated with biochemical progression-free survival, radiological progression-free survival and overall survival. Conclusion: Our findings suggest that FCH-PET/CT may play a role in defining prognosis of patients receiving enzalutamide because baseline SUVmax proved to be an independent prognostic factor.

Aim: To assess clinical outcomes in octogenarians treated with docetaxel (DOC) for metastatic castration-resistant prostate cancer. Patients & methods: The multicenter retrospective study was based on a review of the pre- and post-DOC clinical history, DOC treatment and outcomes. Results: We reviewed the records of 123 patients (median age: 82 years) who received DOC every 3 weeks or weekly, without significant grade 3–4 toxicities. Median progression-free survival was 7 months; median overall survival from the start of DOC was 20 months, but post-progression treatments significantly prolonged overall survival. Conclusion: The findings of this study suggest that toxicity is acceptable, survival is independent of patient's age and survival can be significantly prolonged by the use of new agents.

Background Two new hormonal agents (NHAs), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CABA) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel. Although several analyses of patient cohorts receiving a sequence of two different new agents (NAs) after docetaxel have been published, no definite conclusions can be drawn regarding the best treatment strategy. Materials and methods All published studies reporting monthly OS rates of mCRPC patients receiving third-line NA after having previously received docetaxel and another NA have been analyzed. The treatments were merged into three groups: one NHA followed by another, one NHA followed by CABA, and CABA followed by one NHA. The cumulative monthly OS rates in each group were determined using a weighted-average approach. Results Thirteen retrospective studies including 1016 patients who received NHA/NHA (469), NHA/CABA (318) or CABA/NHA (229) were evaluated. The 12-month OS rates were 28.5%, 61.3%, and 76.4%, respectively. There were no statistically significant differences in terms of known prognostic factors. Conclusions Although the retrospective nature of the studies and potential selection biases, our data seem to confirm the potential cumulative survival benefit of using the NAs sequentially after docetaxel. There was no clear superiority of any one of the three strategies, but a sequence that includes CABA seems to suggest a possible OS advantage.

BACKGROUND: IBC is a heterogeneous disease with several subtypes molecularly identified by gene expression profile. Since subtypes defined by immuhistochemistry (IHC) panel are similar although not identical to molecular subtypes, IHC may represent an easier alternative to identify them. PURPUSE: To assess the clinical outcomes of pts who received NC for IBC and the differences by IHC-related subtypes. METHODS: We retrospectively reviewed the clinical records of the pts treated with NC for stage II-III IBC from 2000 to 2013. For each pt we recorded baseline tumor size, type of NC [which consisted of anthracyclines (A) + taxanes (T) in HER2- and T + trastuzumab (H) ± A in HER2+ pts), type of surgery, pathological response (pCR defined as the absence of invasive cells in the breast and the lymph nodes regardless of DCIS). IHC subtypes were defined according to ER and PgR expression, Ki-67 level, and HER2 status: Luminal A (LA): ER and PR+, neg HER2 and Ki67< 14% (= 3%) Luminal B (LB): ER and/or PR+, neg HER2 and Ki67≥14% (=30%) Luminal HER2 (LHER2): ER and/or PR+, positive HER2 and any Ki67 (=27%) HER2 positive (HER2+): neg ER and PR, positive HER2 and any Ki67 (=12%) Triple negative (TN): neg ER and PR, neg HER2 and any Ki67 (13%) Unknown subtype in 33 cases (15%) The loco-regional and distant RFS and OS were evaluated according to pCR. pCR and survival outcomes were also assessed on the basis of both pre- and post- NC Ki67 levels. RESULTS: In the consecutive series of 213 pts who received NC median age was 50 yrs (r. 25-75). The NC consisted of an A+T based regimen in HER2 negative (145 pts) and of a T+ H with A (31 pts) or without A (34 pts) in HER2+ disease. Only 14 did not receive surgery: 10 for distant metastases development and 4 because still on NC. Quadrantectomy was performed in 120 pts (60%). Among all pts, pCR was achieved in 44 pts(22%) with further 4 pts showing a RT ≤1 mm. Relationship between pCR and subtypes, ki67 and recurrence rate LA (%)LB (%)LHER2 (%)HER2+TN (%)Median Ki67 (%)Recurrence Rate (%)pCR012.542.527.517.5484.5No pCR10042.329.28.814.63731.5p Value All but 19 HER2+ pts (84) received H obtaining pCR in 38% of cases regardless chemotherapy type (A-based 35% vs Not A- 38%) The median follow-up was 45 months (range 1-166 ms). The 4y-RFS and OS were better in which achieved pCR than those did no (RFS 92 vs to 74%; p=0.0014 and OS 95 vs 78%; p=0.0074). Median Ki67 in pretreated core biopsy was 40 compared to 27% in post-NC RT. Patients with high (>30%) post-NC Ki67 levels showed significantly higher risk for disease relapse (4 y-RFS 60%; p=0.0019) and death (4y OS 71%; p=0.018) compared with patients with 15-30 Ki67 levels (4y-RFS 83 and OS 82%). CONCLUSIONS: According to literature data, pts achieving pCR after NC showed better RFS and OS compared to no pCR pts. The pCR rate was significantly higher in aggressive subtypes (HER2 and TN). In HER2 disease, pCR was achieved by using chemo + H, irrespective of A-addition. Interestingly high pre-NC KI67 levels seem to predict the possibility obtaing pCR, while post-NC Ki67 levels seem to be of prognostic value in pts who do not receive pCR. Citation Format: Antonella Ferro, Alessia Caldara, Mariachiara Dipasquale, Chiara Trentin, Renza Triolo, Mattia Barbareschi, Daniela Bernardi, Marco Pellegrini, Daniela Cazzolli, Gabriella Berlanda, Fabio Gasperetti, Francesca Maines, Paolina Tuttobene, Orazio Caffo, Enzo Galligioni. Clinical outcomes according to pathological complete response (pCR) and proliferation index of residual tumor (RT) after neoadjuvant chemotherapy (NC) in invasive breast cancer (IBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-21-06.

ABSTRACT The availability of active new drugs for the treatment of advanced castration-resistant prostate cancer has significantly prolonged overall survival, thus changing the natural history of the disease and raising the likelihood of observing metastases in atypical sites. This review of the literature describes the frequency, clinical-pathological features and presenting symptoms of non-liver gastrointestinal metastases (GIm) from prostate cancer. Its purpose is to increase clinical awareness of the increasing incidence of such GIm, contributing to the early detection, accurate diagnosis and, when feasible, appropriate management.

The introduction of docetaxel into clinical practice and the more recent availability of other active therapeutic options, such as cabazitaxel, abiraterone acetate, enzalutamide and radium-223, have significantly improved the clinical outcomes of patients affected by castration-resistant prostate cancer (CRPC). Bone and nodes metastases are usually the first presentation of advanced disease, but the improvement in overall survival and the greater use of imaging techniques for restaging of metastatic CRPC patients have led to a previously unexpected clinical scenario characterized by an increased incidence of visceral metastases not only in the liver and lungs, but also in atypical sites such as the brain or gastrointestinal tract. We describe a rare case of CRPC metastasizing to the small bowel with particular endoscopic and radiographic findings.

To assess the safety and efficacy of abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated in a compassionate named patient programme (NPP). We retrospectively reviewed the clinical records of patients with mCRPC treated with AA at the standard daily oral dose of 1000 mg plus prednisone 10 mg/day in 19 Italian hospitals. We assessed 265 patients with mCRPC treated with AA. The most frequent (>1%) grade 3–4 toxicities were anaemia (4.2%), fatigue (4.2%), and bone pain (1.5%). The median progression-free survival was 7 months; median overall survival was 17 months after starting AA, and 35 months after the first docetaxel administration. Our study reproduced the clinical outcomes reported in the AA pivotal trial, including those relating to special populations such as the elderly, patients with a poor performance status, symptomatic patients, and patients with visceral metastases. Our data show the safety and activity of AA when administered outside clinical trials, and confirm the findings of the post-docetaxel pivotal trial in the patients as a whole population and in special populations of specific interest.

Background Enzalutamide is active in advanced castration-resistant prostate cancer (CRPC) patients, in whom it has shown to be able to increase survival. We report the enzalutamide effect on primary prostate tumors, assessed by changes of metabolic tumor activity detected by 18F-fluorocholine-positron emission tomography/computerized tomography (18F-FCH PET/CT). Patients and Methods We treated 31 patients with pretreated metastatic CRPC in an enzalutamide named-patient program. All patients were initially evaluated and then followed up by means of repeated 18F-FCH PET/CT examinations. We identified most radiotracer-avid lesions, which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum radiotracer standardized uptake value (SUVmax) and the threshold-based volume of interest (VOI) with a cutoff SUV value ≥ 2.5. In the 12 patients who did not receive a radical treatment for localized disease, the prostate was also considered an ROI. Results The baseline prostate median SUVmax of 7.25 showed reductions of 25% (P = .012) and 43% (P = .009) after 3 and 7 months of enzalutamide treatment, respectively. The baseline median prostate VOI of 12.73 cm3 showed a reduction of 73% (P = .002) at 3 months and a reduction of 90% (P = .005) at 7 months. Conclusion In addition to the metabolic changes of metastatic lesions observed with enzalutamide in CRPC patients, our data have shown significant volume reductions of the primary tumors according to 18F-FCH PET/CT evaluation. These results could suggest the potential of enzalutamide therapy for localized prostate cancer.

// Francesca Lovat 1 , Hideshi Ishii 2 , Monica Schiappacassi 3 , Matteo Fassan 1,4 , Mattia Barbareschi 5 , Enzo Galligioni 5 , Pierluigi Gasparini 1 , Gustavo Baldassarre 3 , Carlo M. Croce 1 and Andrea Vecchione 1,6 1 Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University Wexner Medical Center and Comprehensive Cancer Center, Columbus, Ohio, USA 2 Department of Frontier Science for Cancer and Chemotherapy Osaka University, Japan. 3 Division of Experimental Oncology 2, Centro di Riferimento Oncologico, National Cancer Institute, Aviano, Italy 4 ARC-NET Research Centre, University and Hospital Trust of Verona, Verona, Italy 5 Departments of Pathology and Medical Oncology, Ospedale Santa Chiara, Trento, Italy 6 University of Rome “La Sapienza”, Department of Clinical and Molecular Medicine, Ospedale Santo Andrea, Rome, Italy Correspondence: Andrea Vecchione, email: // Keywords : Lzts1/Fez1; breast cancer; taxanes Received : November 26, 2013 Accepted : December 14, 2013 Published : December 14, 2013 Abstract The Leucine Zipper Tumor Suppressor 1 (LZTS1) is a tumor suppressor gene, located at chromosome 8p22, which is frequently altered in human cancer. In normal tissue, its ubiquitous expression regulates cell mitosis by the stabilization of microtubule networks. LZTS1-deficient mouse embryonic fibroblasts have been shown to have an accelerated mitotic progression, and a higher resistance to taxanes, microtubule-stabilizing drugs. We investigate the role of Lzts1 in paclitaxel-resistance in breast cancer cells. Downregulation of Lzts1 expression significantly decreases sensitivity to paclitaxel in vitro. We further analyzed Lzts1 expression by immunohistochemistry in 270 primary breast cancer samples and 16 normal breast specimens. Lzts1 was significantly downregulated in breast cancer samples and its deregulation was associated with a higher incidence of tumor recurrence, and to a worse overall survival. Moreover, Lzts1-negative tumors were associated with unfavorable outcome after taxanes-based therapy. Thus our data suggest that Lzts1 deregulation is involved in breast cancer and its immunohistochemical evaluation may serve as a prognostic factor for breast cancer therapy

With seven agents approved for metastatic renal cell carcinoma (RCC) within the past few years, there has undoubtedly been progress in treating this disease. The treatment safety of these new agents, however, now represents a crucial concern, which requires a search for the best possible balance between the minimization of the treatment burden and the need for maintaining appropriate drug dosages able to induce the best clinical benefit. In this review we have analyzed safety data of all approved targeted agents for metastatic RCC available as first- or second-line therapy to provide suggestions aimed at establishing the most appropriate second-line or later treatment on the basis of toxicities that have arisen in therapy. Based on the characteristics and comorbidities of the patients and on the toxicity profile of each treatment, it is possible to plan different therapeutic options. We, therefore, have compiled a list of points that are important to keep in mind when considering the use of the targeted drugs for the treatment of advanced RCC.

Non-small-cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers, and one of the leading causes of cancer-related mortality. As most newly diagnosed patients present distant metastases, chemotherapy is the treatment of choice. Chemotherapy also plays a central role in postoperative and radical treatment in addition to radiotherapy.This paper reviews the role of vinorelbine , both alone and in combination with platinum-derivates, in the treatment of NSCLC. The authors review its efficacy at different stages of disease and under different conditions. Specifically, the authors evaluate its pharmacokinetic and toxicity profile and provide insight into its future as an NSCLC therapeutic.In the first-line treatment of advanced NSCLC, the use of vinorelbine-based regimens may be less efficacious in controlling disease than other combinations. However, since their activity is not related to histology, vinorelbine still has potential as a first-line treatment for NSCLC patients in whom histology has failed to distinguish non-squamous from squamous histotypes. The use of an oral formulation may furthermore improve tolerability and patient compliance. Vinorelbine should be the drug of choice in the adjuvant setting as the vinorelbine/cisplatin doublet is the only regimen so far that has led to a survival gain in two Phase III trials. In patients aged70 years, vinorelbine (together with gemcitabine) should furthermore be the reference drug for first- and second-line therapy when single-agent chemotherapy is the treatment of choice. However, new efforts still need to be made to develop oral schedules for NSCLC.

Although radical cystectomy is still the treatment of choice for patients with infiltrating bladder cancer, there is growing evidence of the effectiveness of a conservative approach. Developed as a treatment of need for elderly or unfit patients unable to undergo radical cystectomy, conservative therapy is becoming a true alternative to surgery for highly selected patients. Although transurethral bladder resection, external radiotherapy and systemic chemotherapy can control the disease as single treatments, the best results have been observed when they are combined. Moreover, new irradiation techniques and new-generation drugs are now being tested in an attempt to improve disease control further. Conservative management requires the multidisciplinary involvement of different specialties in order to give patients a real alternative to surgical treatment.

Brain metastases from prostate cancer (PC) seem to be more frequent than in the past, possibly because advances in the treatment of patients with castration-resistant PC have prolonged their survival. Furthermore, docetaxel (the drug of choice for the first-line treatment of castration-resistant PC) cannot cross the blood–brain barrier and control metastatic foci. However, this problem may be overcome by new active drugs such as cabazitaxel.

Although over 70% of patients with metastatic renal cell carcinoma (RCC) respond to initial therapy with tyrosine kinase inhibitors (disease control rate 70-80%), approximately 20-30% of patients do not respond to first-line therapy and progress within ≤3 months. Understanding the mechanisms of resistance to targeted therapies is vital in the development of prospectively defined sequences and because the choice of first-line therapy determines that of second and subsequent line therapy, identification of the optimal first-line therapy is a priority for clinicians treating patients with metastatic RCC. By preselecting those patients most likely to respond to antivascular endothelial growth factor therapy, clinicians can begin to optimize therapeutic strategies. This review focuses on primary antivascular endothelial growth factor-refractory patients and the move towards individualizing treatment for RCC. The authors include a review of the growing number of studies, as yet retrospective, which provide important information on the group of primary refractory patients with advanced RCC for whom the prognosis is not good. First, the percentage of primary refractory patients (26%) is in agreement with disease control rate - the sum of objective responses and disease stabilization, observed in registration studies for a range of tyrosine kinase inhibitors. Second, the prognosis for these patients is poor as they do not respond to first-line nor to second-line therapy, and changing the mechanism of action (with inhibition of mTOR pathway) does not appear to produce additional benefits. Third and most importantly, the results of these studies demonstrate the need to better characterize the mechanism of primary resistance to current therapeutic agents with the ultimate aim of developing a therapeutic strategy for this important subgroup of patients.

International audience; PURPOSE:Although radical cystectomy is still considered the standard of care for most localized muscle-invasive bladder cancer (MIBC) patients, bladder-sparing strategies with chemoradiotherapy have demonstrated comparable local control and survival rates when adjusting for tumor stage. We present a pooled analysis of individual patient data out of published trials with gemcitabine-based chemoradiotherapy for MIBC.METHODS AND MATERIALS:Individual patient data were collected from Institutions that enrolled patients into trials that evaluated gemcitabine-based chemoradiotherapy for MIBC.RESULTS:We identified eight studies published on gemcitabine-based radiochemotherapy and 190 patients were included in this analysis. A complete response (CR) was observed in 166 patients (93%). After a median follow up of 44.5months, 36 patients (18.9%) presented a bladder recurrence and 14 subsequently underwent cystectomy. The 5-year overall survival (OS), disease-specific survival (DSS), and cystectomy-free survival (CFS) rates were 59%, 80.9%, and 93.3%, respectively. The achievement of CR after chemoradiotherapy was the main prognostic variable which was associated with improved OS, DSS, and CFS. The treatment was well tolerated.CONCLUSION:This pooled analysis strengthens the evidence that chemoradiotherapy regimens with concurrent gemcitabine are feasible and well tolerated. Prospective randomized controlled trials are on-going to definitively assess the efficacy of gemcitabine-based chemoradiotherapy for MIBC.

It has recently been reported that the incidence of brain metastases (BMs) from prostate cancer (PC) has increased in comparison with historical series. The aim of this study was to compare the incidence of BMs in the pre- and post-docetaxel era in a single institution in which all oncological patients are referred to one Radiotherapy and one Medical Oncology Department. We searched the electronic databases of these departments for all males with BMs entered from 1994 to 2011. The year of the introduction of docetaxel into clinical practice (2002) divided the observation period into two 9-year periods: period 1 (P1) from 1994 until 2002 (P1), and period 2 (P2) after 2002. The number of patients with BMs was constant: 241 patients in P1 and 249 in P2. The greatest changes in frequency between P1 and P2 involved colorectal cancer (+75.9 %), renal cancer (+141.9 %), and PC (+238.7 %). The total number of patients with BMs from PC was nine: two in P1 (0.8 %) and seven in P2 (2.8 %). All but two of these patients developed BMs after becoming castration-resistant. Median BM-free survival was 36 months, whereas median BM survival was 8 weeks. As the appearance of BMs in the natural history of PC is usually related to the late phase of the disease, and mortality due to PC remained constant, it seems that there really has been an increase in the frequency of BMs from PC that may reflect a gain in survival.

Sequencing decisions in advanced renal cell carcinoma are likely to become more difficult when new targeted agents are approved for first and subsequent lines of therapy. Approximately 70% of patients benefit from targeted therapy before progression, of which 20% can be described as short-term responders (progression-free survival:6 months) and 50% as long-term responders (progression-free survival:6 months). The remaining 30% show either no response (20%) or are intolerant to treatment (10%). The challenge is to establish the optimal second-line agent for over 70% of patients who progress following initial response to a first-line tyrosine kinase inhibitor. As it is impossible to define the optimal second-line therapy for every patient, it is suggested that age and comorbidities of the patient, the sites of disease and the side effects of previous therapies be taken into account in order to optimize the use of different agents sequentially.

Objective To describe the feasibility and efficacy of multiple sequential rechallenges and analyze the predictive factors that may aid in selecting patients who are more likely to respond. Several studies have demonstrated the feasibility and activity of a single docetaxel rechallenge in patients with castration-resistant prostate cancer (CRPC), thus providing an additional opportunity for treatment in docetaxel-sensitive CRPC patients in clinical practice. Materials and Methods CRPC patients who completed first-line docetaxel therapy without disease progression have been offered a docetaxel rechallenge, and the responders have undergone further rechallenges until the appearance of docetaxel resistance. We assessed their clinical outcomes and evaluated all the variables potentially capable of predicting the response to rechallenge by means of uni- and multivariate analysis. Results Forty-six consecutive patients underwent 92 rechallenges. The overall biochemical response rate (prostate-specific antigen [PSA] reduction >50%) was 66%. Median overall survival was 32 months with a projected 2-year overall survival from the first docetaxel administration of 77.5%. Multivariate analysis showed that the time slope-log PSA, the time from the previous cycle, and the response to the previous cycle were predictive of the response to a rechallenge. Conclusion A docetaxel rechallenge may be safely repeated several times in CRPC patients and in selected patients could improve disease control. The predictive factors found in our analysis may help select the most appropriate strategy in the light of the availability of active second-line drugs.

Background Early invasive breast cancer (EIBC) is an heterogeneous disease. Immunohistochemical (IHC) markers can be used to classify tumors in different biological subtypes with different clinical behavior. Purpose: The aim of our study was to evaluate survival outcomes for patients (pts) with different subtypes of EIBC as classified using four ICH markers (ER, PR, HER2 and Ki67). Methods: We evaluated data from 3403 consecutive cases of EIBC treated from 1995 to 2008 and classified as: luminal A (positive ER and PR, negative HER2 and Ki67< 14%), luminal B (positive ER and/or PR, negative HER2 and Ki67>14%), luminal C (positive ER and/or PR, positive HER2, any Ki67), HER2+ (negative ER and PR, positive HER2, any ki67), triple negative (negative ER and PR, negative HER2, any ki67). Log-rank test and Kaplan-Meyer estimator were performed to evaluate the impact of ICH subtypes on overall survival (OS), Event Free Survival (EFS) and their correlation with other known prognostic factors such as N, G, Size, Age. Results: We identified 917 luminal A (26.9%), 1731 luminal B (50.9%), 279 (8.2%) luminal C, 183 HER2 + (5.4%) and 293 triple negative (8.6%). Median age was 61 years. Luminal A was more frequently (p Considering only Luminal subtypes, Luminal B and C were significantly associated with poor EFS vs Luminal A EIBCs in both N0 (p=0.046) and N+ pts (p Conclusions: Luminal A showed better prognosis in term of EFS and OS than other subtypes regardless other prognostic factors as clinical features (age) and tumor extent (T and N). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-23.

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75 mg/m(2) cisplatin plus 75 mg/m(2) docetaxel, both administered on day 1 every 21 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm A), or three cycles of 25 mg/m(2) cisplatin plus 25 mg/m(2) docetaxel on days 1, 8 and 15 every 28 days, followed by three cycles of 1,200 mg/m(2) gemcitabine on days 1 and 8 every 3 weeks (arm B).Of the evaluable patients, 61% in arm A (n = 41) and 36% (n = 44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3 months in arm A, respectively, 3.1 and 7.7 months in arm B. Grade 3-4 adverse events were more common in arm A. Grade 3-4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B).Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Data on quality of life during docetaxel treatment in castration resistant prostate cancer was mainly provided by SWOG and TAX327 trials. In the TAX327 trial biochemical response and pain predicted survival, whereas quality of life outcomes did not. In the present study, there were no statistically significant changes in the quality of life scales during treatment except in the case of patients receiving docetaxel and estramustine, who experienced a significant decrease in pain. Our data seem to suggest that patients with a better baseline quality of life (and consequently with fewer symptoms) are more likely to achieve a biochemical response. OBJECTIVES • To assess quality of life (QoL) outcomes and pain changes in patients affected by castration-resistant prostate cancer enrolled in a phase II randomized trial of 3-week docetaxel (DOC)-based chemotherapy. • To provide further data to clarify the conflicting published data concerning the impact of DOC on the patients’ QoL. PATIENTS AND METHODS • QoL outcomes were assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 questionnaire. • Pain changes were evaluated by means of the Brief Pain Inventory at baseline and after every two DOC courses. • The patients completing at least two questionnaires (at baseline and before the third course) were considered evaluable. RESULTS • In all, 59 patients were evaluable. • Asymptomatic patients and responders had a better baseline QoL than symptomatic patients and non-responders. • There were no statistically significant changes in the QLQ-C30 scales during treatment except in the case of patients receiving DOC and estramustine, who experienced a significant decrease in pain. • There was a progressive improvement in the mean intensity and interference scores of the Brief Pain Inventory. CONCLUSIONS • Our data confirm that QoL is generally maintained during chemotherapy. • There is a substantial reduction in pain. • Our results also suggest that baseline QoL may predict treatment response.

PURPOSE: To examine interactions between mib-1 and clinical-pathological markers and their impact on outcomes. PATIENTS AND METHODS: Mib-1 was identified by immunohistochemical staining in 3402 EIBC pts treated from 1995 to 2008. Mib-1 was defined as low (15%), intermediate (16%-30%) and high (>30%) value. Correlation between mib-1 and age, tumor size (T), nodal status (N), ER, PR, HER-2, grading (G) was performed by X2 test. Log-rank test and Cox regression model were performed to test mib-1 as prognostic factor for overall survival (OS) and Disease Free Survival (DFS) and its correlation with other known prognostic factors. RESULTS: Median mib-1 was 25%. Mib-1 was low in 1135, intermediate in 1094 and high in 1173 pts. Median age was 62 years. High mib-1 was significantly (P DFS and OS (P 40 years pts (P25%) resulted a prognostic factor of worse outcome (P CONCLUSIONS: In our experience, Mib-1 confirms to be a significant prognostic biomarker for DFS and OS in EIBC, providing additional information besides other clinico-pathological parameters to help decision-making of treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-14.

BACKGROUND: Cystectomy is the standard treatment for patients with infiltrating bladder cancer, but conservative treatment with cystoscopic resection followed by radiochemotherapy may be an alternative for highly selected patients. The addition of gemcitabine to cisplatin and radiotherapy may enhance disease control. METHODS: The long-term clinical outcomes of 26 patients enrolled in a previously published dose-finding study and a prematurely discontinued phase 2 trial were evaluated. All the patients underwent transurethral tumor resection followed by a radical dose of external radiotherapy administered at the same time as cisplatin and weekly gemcitabine therapy. RESULTS: After a median follow-up of 74 months, the projected 5-year clinical outcomes were a 70.1% overall survival rate, a 78.9% disease-specific survival rate, and a 73.8% bladder-intact survival rate. CONCLUSIONS: The long-term follow-up data from the current study confirmed that the addition of gemcitabine to radiotherapy and cisplatin is safe and leads to good local and distant disease control. The concomitant administration of cisplatin may explain the good long-term organ preservation that was observed. Conducting confirmatory and comparative trials could satisfy an unmet need but requires the multidisciplinary cooperation of urologists in selecting the right patients for a bladder-sparing strategy. Cancer 2011. © 2010 American Cancer Society.

Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m(2)/min could be more effective than when administered as the standard 30-min infusion, the available pharmacokinetic data are still too limited to draw definitive conclusions. This study is aimed to investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given as FDR at doses of 600 and 1,200 mg/m(2) in combination with 75 mg/m(2) of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients.The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m(2) gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m(2) gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m(2)/min on days 1 and 8 of a 21-day cycle (at first cycle). At the second cycle, all patients were treated with gemcitabine at 1,200 mg/m(2) 120-min i.v. infusion (FDR of 10 mg/m(2)/min) on days 1 and 8 of a 21-day cycle. At each cycle, gemcitabine was administered alone on day one, and in combination with 75 mg/m(2) of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic analyses were performed on blood samples collected at defined time points before, during and after gemcitabine infusion.The plasmatic pharmacokinetic parameters were clearly different when the patients received a higher gemcitabine dose in the second cycle compared to the lower dose of the first course; in the same time, the intracellular drug levels were not modified. Comparing the pharmacokinetic parameters of different patients treated at different dose levels, the results appeared to be quite similar.A substantially higher accumulation of metabolites in peripheral blood mononuclear cells was observed when the longer infusion time was employed, suggesting a pharmacological advantage for this treatment schedule.

OBJECTIVE To report the results of a randomized phase II trial of docetaxel with and without estramustine phosphate (EP) in patients with hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS Patients with progressive HRPC were randomized to receive docetaxel 70 mg/m2 on day 1 (arm A), or docetaxel 70 mg/m2 on day 2 plus oral EP three times daily, at a total daily dose of 840 mg, on days 1–5 (arm B). The primary objective of the trial was to evaluate the activity of the treatments in terms of the response in prostate-specific antigen (PSA) level. RESULTS Forty-five of the 49 patients centrally randomized to arm A and 44 of the 46 in arm B were evaluable for activity. The PSA level decreased by ≥50% in 40% of the patients in arm A and in 75% of those in arm B. The median time to PSA progression was 20 weeks in arm A and 30 weeks in arm B. The patients in arm B had an improvement in pain over time. CONCLUSION These data support the existence of a possible advantage in combining docetaxel and EP, which should be verified in a specific randomized phase III study.

Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC) is a pyrimidine antimetabolite employed against several human malignancies. It undergoes intracellular activation to the pharmacologically active triphosphate form (dFdCTP) and metabolic inactivation to the metabolite 2',2'-difluorodeoxyuridine (dFdU). In order to investigate the human plasma pharmacokinetics of dFdC and dFdU, we developed and validated an HPLC-MS/MS method, adding 2'-deoxycytidine as internal standard and simply precipitating the protein with acetonitrile. The method requires a small sample (125 microl), and it is rapid and selective, allowing good resolution of peaks from the plasma matrix in only 7 min. It is sensitive, precise and accurate, with overall precision, expressed as CV%, always less than 10.0% for both analytes and high recovery: > or = 80%. The limits of detection for dFdC and dFdU were 0.1 and 1.1 ng/ml, but considering the high concentrations in the plasma of patients investigated, we set the limit of quantitation at 20 ng/ml (0.08 microM) for dFdC and 250 ng/ml for dFdU, and validated the assay up to the dFdC concentration of 6.0 microg/ml (22.8 microM). The method was successfully used to study the drug pharmacokinetics in patients with advanced non-small-cell lung cancer in a phase II trial with gemcitabine administered as a fixed dose-rate infusion.

Background To assess the relationship between dosimetric parameters and the quality of life (QL) outcomes of patients with low-intermediate-risk localised prostate cancer (LPC) treated with low-dose-rate brachytherapy (LDR-BT). Materials and methods We evaluated the participants in two consecutive prospective studies of the QL of patients treated with LDR-BT for LPC. QL was evaluated by means of a patient-completed questionnaire assessing non functional [physical (PHY) and psychological (PSY) well-being, physical autonomy (POW), social relationships (REL)] and functional scales [urinary (URI), rectal (REC), and sexual (SEX) function]; a scale for erectile function (ERE) was included in the second study. Urethra (D10 ≤ 210 Gy) and rectal wall constraints (V100 ≤ 0.5 cc) were used for pre-planning dosimetry and were assessed with post planning computerized tomography one month later for each patient. Results QL was assessed in 251 LPC patients. Dosimetry did not influence the non-functional scales. As expected, a progressive impairment in sexual and erectile function was reported one month after LDR-BT, and became statistically significant after the third year. Rectal function significantly worsened after LDR-BT, but the differences progressively decreased after the 1-year assessment. Overall urinary function significantly worsened immediately after LDR-BT and then gradually improved over the next three years. Better outcomes were reported for V100 rectal wall volumes of ≤ 0.5 cc and D10 urethra values of ≤ 210 Gy. Conclusions The findings of this study show that dosimetric parameters influence only functional QL outcomes while non-functional outcomes are only marginally influenced.

Metastatic castration-resistant prostate cancer mainly affects older men, opening issues about the efficacy and safety of therapies in this population. We have demonstrated that abiraterone, a selective androgen biosynthesis inhibitor, is a safe and active therapeutic option in a subgroup of 47 very elderly adults (aged80 years) enrolled in the Italian named patient program, with a tolerability profile and clinical outcomes comparable to those of younger population.Prostate cancer mainly affects elderly men, who are often frail and whose reduced physiological reserves and multiple comorbidities increase the risk of side effects. The availability of new drugs has improved the overall survival (OS) of patients with castration-resistant prostate cancer (CRPC) but has increased the number of very elderly CRPC patients receiving anticancer drugs, raising questions about their efficacy and safety in this population.We assessed the tolerability of abiraterone (AA) in a cohort of very elderly adults with metastatic CRPC (mCRPC) enrolled in the Italian AA named patient program and analyzed their clinical outcomes. We retrospectively reviewed the clinical records of 47 mCRPC patients aged80 years who had received AA after docetaxel. The Kaplan-Meier method was used to calculate OS and progression-free survival (PFS). Safety and clinical outcomes were also analyzed by age group (80 and80 years). Cox regression analysis was used to calculate the differences in PFS and OS between the groups according to the stratification variables.In very elderly men, the prostate-specific antigen response rate was 48.9%, and the median PFS and OS were 8 and 18 months, respectively. The differences in toxicities between the older and younger age groups were not major. The limitation of the present study was mainly its retrospective nature.Our data show that AA is active and safe in very elderly patients and leads to outcomes similar to those observed in younger patients, thus confirming that AA is a manageable therapeutic option for this patient population.

The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naive patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.

BackgroundThe potential benefits of the introduction of electronic and mobile health (mHealth) information technologies, to support the safe delivery of intravenous chemotherapy or oral anticancer therapies, could be exponential in the context of a highly integrated computerized system. ObjectiveHere we describe a safe therapy mobile (STM) system for the safe delivery of intravenous chemotherapy, and a home monitoring system for monitoring and managing toxicity and improving adherence in patients receiving oral anticancer therapies at home. MethodsThe STM system is fully integrated with the electronic oncological patient record. After the prescription of chemotherapy, specific barcodes are automatically associated with the patient and each drug, and a bedside barcode reader checks the patient, nurse, infusion bag, and drug sequence in order to trace the entire administration process, which is then entered in the patient’s record. The usability and acceptability of the system was investigated by means of a modified questionnaire administered to nurses. The home monitoring system consists of a mobile phone or tablet diary app, which allows patients to record their state of health, the medications taken, their side effects, and a Web dashboard that allows health professionals to check the patient data and monitor toxicity and treatment adherence. A built-in rule-based alarm module notifies health care professionals of critical conditions. Initially developed for chronic patients, the system has been subsequently customized in order to monitor home treatments with capecitabine or sunitinib in cancer patients (Onco-TreC). ResultsThe STM system never failed to match the patient/nurse/drug sequence association correctly, and proved to be accurate and reliable in tracing and recording the entire administration process. The questionnaires revealed that the users were generally satisfied and had a positive perception of the system’s usefulness and ease of use, and the quality of their working lives. The pilot studies with the home monitoring system with 43 chronic patients have shown that the approach is reliable and useful for clinicians and patients, but it is also necessary to pay attention to the expectations that mHealth solutions may raise in users. The Onco-TreC version has been successfully laboratory tested, and is now ready for validation. ConclusionsThe STM and Onco-TreC systems are fully integrated with our complex and composite information system, which guarantees privacy, security, interoperability, and real-time communications between patients and health professionals. They need to be validated in order to confirm their positive contribution to the safer administration of anticancer drugs.

ABSTRACT Aims: The intermittent administration of chemotherapy is a means of preserving patients’ quality of life (QL). The aim of this study was to verify whether the intermittent administration of docetaxel (DOC) improves the patients’ QL. Patients & methods: All patients received DOC 70 mg/m2 every 3 weeks for eight cycles. The patients were randomized to receive DOC continuously or with a fixed 3-month interval after the first four DOC courses. Results: The study involved 148 patients. There was no difference in QL between the groups receiving intermittent or continuous treatment. Intermittence had no detrimental effects on disease control. Conclusion: Although feasible and not detrimental, our results showed that true intermittent chemotherapy in metastatic castration-resistant prostate cancer patients failed to improve the patients’ QL.

Background The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. Objective To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. Design, setting, and participants We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. Outcome measurements and statistical analysis The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. Results and limitations We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. Conclusions We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. Patient summary It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent.

Purpose: Permanent interstitial brachytherapy (IB) has become an increasingly appealing therapeutic option for localized prostate cancer (LPC) among physicians and patients because it involves short hospitalization and treatment and its postulated low degree of toxicity may reduce its impact on the patients’ quality of life (QoL). The aim of this prospective study was to assess the impact of IB on the QoL of patients with LPC. Methods and Materials: A validated self-completed questionnaire was administered to the patients before and after IB and then at yearly intervals. The items allowed the identification of seven subscales exploring physical well-being (PHY), physical autonomy (POW), psychological well-being (PSY), relational life (REL), urinary function (URI), rectal function (REC), and sexual function (SEX). Results: The assessment of the QoL of 147 patients treated between May 2000 and February 2005 revealed no relevant differences in the PHY scale scores 1 month after IB or later, and the same was true of the POW, PSY, and REL scales. Urinary function significantly worsened after IB and returned to pretreatment levels only after 3 years; the impact of the treatment on the URI scale was greater in the patients with good baseline urinary function than in those presenting more urinary symptoms before IB. Rectal and sexual functions were significantly worse only at the post-IB evaluation. Conclusions: The results of the present study confirm that the impact of IB on the patients’ QoL is low despite its transient negative effects on some function, and extend existing knowledge concerning QoL after IB.

PurposeUGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.Patients and MethodsIn a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment. UGT1A1*28 polymorphism was investigated with respect to the distribution of hematologic and nonhematologic toxicity, objective response rate, and survival. Pharmacokinetics was investigated in a subgroup of patients (71 of 250) who had been analyzed with respect to toxicity and efficacy.ResultsUGT1A1*28 polymorphism was associated with a higher risk of grade 3 to 4 hematologic toxicity (odds ratio [OR], 8.63; 95% CI, 1.31 to 56.55), which was only relevant for the first cycle, and was not seen throughout the whole treatment period for patients with both variant alleles TA7/TA7compared with wild-type TA6/TA6. The response rate was also higher in TA7/TA7patients (OR, 0.32; 95% CI, 0.12 to 0.86) compared with TA6/TA6. A nonsignificant survival advantage was observed for TA7/TA7when compared with TA6/TA6patients (hazard ratio, 0.81; 95% CI, 0.45 to 1.44). Higher response rates were explained by a different pharmacokinetics with higher biliary index [irinotecan area under the curve (AUC)×(SN38 AUC/SN38G AUC)] and lower glucuronidation ratio (SN38G AUC/SN38 AUC) associated with the TA7/TA7genotype and a higher response rate, indicating that the polymorphism is functionally relevant.ConclusionThe results indicate that UGT1A1*28 polymorphism is of some relevance to toxicity; however, it is less important than discussed in previous smaller trials. In particular, the possibility of a dose reduction for irinotecan in patients with a UGT1A1*28 polymorphism is not supported by the result of this analysis.

230 Background: High NLR has been reported to be a poor prognostic indicator in both first and second mCRPC lines, while no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcomes and NLR in a series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 476 mCRPC pts with bone (86%), nodal (56%) or visceral (15%) mets, was collected. All pts received a NA-based third line: 135 received AA, 221 CABA and 120 ENZ. Data on NLR were available for 398 pts (84%). In the univariate analyses, the NLR as a discrete variable dichotomized according to the Maximally Selected Log-Rank statistics (optimal cut-off: 3.66), was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001). At the multivariate analysis, NLR, performance status, pain, hemoglobin, alkaline phosphatase, treatment with AA and with CABA were independent prognostic factors for PFS, while NLR, performance status, hemoglobin, PSA, and lactate dehydrogenase were independent prognostic factors for OS . In Kaplan-Meier analysis, the median OS from the start of third-line was higher (14.2 vs 9.3 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 5.5 and 3.8 (log-rank; P < 0.0001) in pts with NLR ≤ 3.66 and > 3.66, respectively. Conclusions: Our results, observed in the largest cohort of mCRCP pts treated with NA-based third line after DOC and another NA, confirms that NLR is an independent factor for PFS and OS also in this population.

To assess the safety and efficacy of abiraterone acetate (AA) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated in a compassionate named patient programme (NPP).We retrospectively reviewed the clinical records of patients with mCRPC treated with AA at the standard daily oral dose of 1000 mg plus prednisone 10 mg/day in 19 Italian hospitals.We assessed 265 patients with mCRPC treated with AA. The most frequent (1%) grade 3-4 toxicities were anaemia (4.2%), fatigue (4.2%), and bone pain (1.5%). The median progression-free survival was 7 months; median overall survival was 17 months after starting AA, and 35 months after the first docetaxel administration. Our study reproduced the clinical outcomes reported in the AA pivotal trial, including those relating to special populations such as the elderly, patients with a poor performance status, symptomatic patients, and patients with visceral metastases.Our data show the safety and activity of AA when administered outside clinical trials, and confirm the findings of the post-docetaxel pivotal trial in the patients as a whole population and in special populations of specific interest.

ABSTRACT: Aim: To identify factors predicting primary resistance to new-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Patients & methods: Our hospital has conducted two successive named patient NHA programs. A total of 57 patients with progressive CRPC previously treated with first-line docetaxel-based chemotherapy received standard NHA doses: abiraterone acetate 1000 mg once-daily combined with prednisone (5 mg twice daily) or enzalutamide 160 mg once-daily. Patients, who were assessed monthly to check their hematological parameters and prostate-specific antigen (PSA) levels, also underwent imaging investigations every 3–4 months. In total, 24 variables were assessed as potential predictors of primary NHA resistance. Results: Univariate analysis indicated that baseline pain and lactate dehydrogenase levels, and PSA levels after 1 month’s treatment were predictive of primary NHA resistance. Only the predictive value of PSA levels after 1 month of treatment was confirmed at multivariate analysis. This factor strongly predicted progression-free and overall survival. Conclusion: Results suggest the use of a simple and rapid method of identifying patients with primary resistance to NHAs: patients not achieving a ≥50% reduction in PSA levels within the first treatment month should undergo intensive investigations to verify whether they have primary resistance to NHAs.

Aim: The Italian Retrospective Analysis of Sorafenib as First or Second Target Therapy study assessed the efficacy and safety of sorafenib in metastatic renal cell carcinoma patients treated in the community. Patients & methods: Patients receiving first- or second-line single-agent sorafenib between January 2008 and December 2010 were eligible. Retrospective data collection started in 2012 and covers at least 1-year follow-up. The primary end point was overall survival (OS). Results: Median OS was 17.2 months (95% CI: 15.5–19.6): 19.9 months (95% CI: 15.9–25.3) in patients treated with first-line sorafenib and 16.3 months (95% CI: 13.1–18.2) with second-line sorafenib. Overall median (95% CI) progression-free survival was 5.9 months (95% CI: 4.9–6.7): 6.6 (95% CI: 4.9–9.3) and 5.3 months (95% CI: 4.3–6.0) in first- and second-line patients, respectively. Conclusion: The efficacy and safety of sorafenib in routine community practice was generally good, especially in relation to OS in patients treated in the second line, where results were similar to those seen in recent prospective clinical trials.

Background The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). Patients and methods In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rIL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 106 IU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-α at a daily dose of 6 x 106 IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. Results Twenty-three percent (95% CI: ± 17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI: ± 11.9) and 9% (95% CI: ± 11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine, months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. Conclusions Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

In the phase III trial comparing 2 docetaxel schedules (3-weekly versus 2-weekly) as first-line chemotherapy for CRPC, recently published in The Lancet Oncology, fewer serious adverse events, particularly hematologic toxicities, and longer times on treatment, in favor of the 2-weekly regimen are reported.1,2,3

Renal cancer cells from 43 patients and normal renal cells from 10 of them were studied for the expression of highly stress-inducible heat shock protein 72 (HSP72) by means of immunoperoxidase analysis. It was found that HSP72 was expressed in a significantly higher percentage of renal cancer cells than normal renal cells (P = 0.0001), the mean percentage of positive cells being 33.1 +/- 18% and 8 +/- 5%, respectively. Moreover, a percentage of HSP72-positive cells that was less than the cut-off point (18%, mean value of normal cells +2 S.D.) significantly correlated with shorter disease-free survival (P = 0.002). The renal cancer cell populations taken from the 21 patients who relapsed after a median time of 13 months (range 3-73 months) had a significantly lower percentage of HSP72-positive cells (mean value 25.1 +/- 17%) than the cells taken from the patients who remained tumour-free (mean value 40.8 +/- 15%) after a median period of 72 months (range 19-96 months, P = 0.003). It was also demonstrated that HSP72 expression can be significantly increased by 48-h in vitro incubation with rIFN-gamma (P = 0.007). These data suggest that HSP72 may represent a favourable prognostic factor regardless of stage and histological grade and its expression may be increased by treatment with rIFN-gamma. Further studies are needed in order to investigate the relationship between HSP72 and the immunoeffector cells.

Patients with refractory metastatic renal cell carcinoma (RCC) were enrolled in a phase II study with teniposide (VM26) and cyclosporin A (CSA) to investigate (1) the effect of CSA on the response rate to VM26; and (2) the effect of CSA on the pharmacokinetics and pharmacodynamics of VM26. Sixteen patients initially received VM26 alone (200 mg m(-2) day(-1) i.v.). No objective responses were observed and all patients crossed over to receive at least an additional two courses (range 2-5) of VM26 plus CSA (5 mg kg(-1) 2h(-1) followed by 30 mg kg(-1) 48h(-1) i.v.). At the end of the 2-h loading dose of CSA, whole-blood CSA levels ranged from 2250 to 3830 ng ml(-1), whereas at the end of the 48-h CSA infusion, CSA ranged from 1830 to 4501 ng ml(-1). CSA significantly (P

Serum interleukin-6 (IL-6) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assay in 62 renal cancer patients: 30 were tumor-free after radical nephrectomy and 32 presented with metastatic disease. Serum IL-6 was undetectable in all but one of the tumor-free patients, whereas 41% (13 of 32) of the metastatic patients presented serum IL-6 levels. Furthermore, there was a significant correlation between serum IL-6 levels and a shorter overall survival (p = 0.009). Moreover, serum sICAM-1 levels were significantly higher (p = 0.05) in the metastatic patients with detectable serum IL-6 than in those without IL-6, suggesting a possible link between IL-6 and sICAM-1. The probability of a shorter overall survival was greater in the metastatic patients with both serum IL-6 and elevated sICAM-1 levels (>635 ng/ml), than in those with elevated sICAM-1 but without IL-6 (p = 0.01). The production of IL-6 by 16 freshly dissociated renal cancer cells cultured in vitro was also observed. It appeared that IL-6 levels did not correlate with the expression and release of ICAM-1 by cultured cells, although the highest values of ICAM-1 release were found in cultures synthesizing the highest values of IL-6. In conclusion, in vivo presence of serum IL-6 and elevated sICAM-1 levels is related to an unfavorable prognosis; it can be speculated that the cells capable of releasing high levels of sICAM-1 and IL-6 may negatively influence the antitumor response.

PI3K/AKT/mTOR pathway alterations are frequent in patients with infiltrating breast cancer (IBC). Their clinical and pathological relevance has been insufficiently documented. We evaluated PI3KCA for mutations and the expression of PTEN, AKT, mTOR and p70S6K by immunohistochemistry in 246 IBC patients treated with hormone therapy (median follow-up, 97 months). A PI3KCA mutation was observed in 50 out of 229 informative cases (21.8 %), PTEN loss in 107 out of 210 (51 %), moderate/high level of expression of AKT in 133 out of 188 (71 %), moderate/high level of expression of mTOR in 173 out of 218 (79 %) and moderate/high level of expression of p70S6K in 111 out of 192 cases (58 %). PI3KCA mutation was associated with the absence of Her2/neu amplification/overexpression and a low level of MIB1/Ki-67 labelling. The expression of p70S6K was associated with a high level of mTOR immunoreactivity, and high PTEN expression was associated with high AKT expression level. Univariate analysis showed that PI3KCA mutation status was not associated with clinical outcome in the series as a whole or in the node-negative subgroup. However, in the node-positive subgroup, exon 9 PI3KCA mutation was associated with unfavourable overall survival (OS), although its impact on the final model in multivariate analysis seemed to be limited. Of the other markers, only high p70S6K expression was associated with a significantly prolonged OS. PI3KCA mutation status is of limited prognostic relevance in oestrogen receptor-positive breast cancer patients treated with hormone therapy.

Clinical Practice Points The availability of new drugs for castration-resistant prostate cancer patients might open new clinical scenarios that are unexpected. The withdrawal syndrome is a well known occurrence after antiandrogen therapy but is not described with use of the new drugs that act on androgen metabolism. It is usually unable to produce an instrumentally detectable improvement of the disease. We describe 2 cases of patients with castrationresistant, metastatic prostate cancer who experienced an abiraterone acetate (AA) withdrawal syndrome, and achieved a metabolic response. We obtained serial prostate-specific antigen (PSA) measurements and choline positron emission tomography/computed tomography (cPET/CT) scans to assess the patients’ response to AA withdrawal. The described patients stopped taking AA because of lack of biochemical response and progression occurrence visualized on cPET/CT scans. Before the start of new treatment, their PSA levels decreased and they remained using no therapy. After 3 months, we observed a progressive additional PSA reduction and a repeated cPET/CT scan revealed an improvement. This is the first report of a long-term withdrawal syndrome and a metabolic response after AA withdrawal. It seems to represent a rare new clinical scenario that might delay the introduction of additional treatment lines. Our findings suggest that it might also lead to a measurable improvement in disease.