A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. PATIENTS AND METHODS: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. RESULTS: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. CONCLUSION: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.

A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer.

BACKGROUND: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition. PATIENTS AND METHODS: We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry. RESULTS: Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively). CONCLUSION: Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way. TRIAL REGISTRATION: ClinicalTrials.gov NCT01254864.

Breast cancer care in northern Ethiopia - cross-sectional analysis.

BACKGROUND: In Ethiopia, the incidence of new cases of breast cancer is currently increasing resulting to high rates of morbidity and mortality. Breast cancer is by far the most common cancer accounting for more than one out of three cancer cases in women and one out of every five in the general population. The study was conducted in University of Gondar Hospital cancer center, located in the North-West Ethiopia; to evaluate the clino-pathologic characteristics of breast cancer and care provided for patients. METHODS: All biopsy proven breast cancer patients treated between 2016 and 2017, were identified and information regarding histology, stage, therapeutic procedure and follow up was retrospectively collected from their individual medical records and descriptive analysis was done. RESULTS: Among 82 patients treated, 67 (82%) were women and 15 (18%) were men. The median age at the time of diagnosis was 45 years (25-82 years). Operation was performed for 56 (68%) patients. The predominant histology was ductal carcinoma in 61 patients (74%), followed by breast carcinoma of No Special Type (NST) in 17 (21%). The late presentation of the patients and the advanced stage at the time of presentation was observed in most of the patients. Chemotherapy was administered in 79 (96%) patients. Radiotherapy was not available in the hospital. CONCLUSION: Breast cancer incidence is rising and becoming a major public health problem in Northern Ethiopia. Breast cancer care in northern-Ethiopia is limited in terms of both pathology, imaging and the offered treatment modalities, which need to be improved.

Clinical trials involving positron emission tomography and prostate cancer: an analysis of the ClinicalTrials.gov database.

BACKGROUND: The goal of this study is to evaluate the status and future perspectives of clinical trials on positron emission tomography in prostate cancer for diagnostic or therapeutic as well as for surveillance purposes. METHODS: The www.ClinicalTrials.gov database was searched on the 20th of January 2017 for all trials containing terms describing "prostate cancer" (prostate, prostatic, malignant, malignancy, cancer, tumor) and "positron emission tomography". In total 167 trials were identified. Trials that included diseases other than PCa were excluded (n = 27; 16%). Furthermore, we excluded trials (n = 4, 2%) withdrawn prior to first patient enrollment. The remaining trials (n = 137, 82%) were selected for further manual classification analysis. RESULTS: One hundred thirty-seven trials were detected and analyzed. Majority of trials were in "active" recruitment status (n = 46, 34%) followed by trials that had been "completed" - (n = 34, 25%) and trials with "closed recruitment but active follow-up" (n = 23, 17%). Phase 1 and 2 comprised 46% of the complete trial portfolio. Locally confined disease was of major interest (n = 46, 34%), followed by metastatic disease - not otherwise specified (n = 43, 13%). Evaluation of PET was the primary goal of the trial in 114 (83%) cases. Most of the trials evaluated only one agent (n = 122, 89%). Choline and PSMA represented two major groups (total 50%) and they were equally distributed across trial portfolio with 25% (n = 34) each. PSMA trials showed the highest average annual growth rate of 56%. The trials were conducted in 17 countries. CONCLUSION: The scientific community is showing a strong and ever-growing interest in the field and we expect that in the coming years, more phase III trials will be initiated ultimately delivering the required Level 1 evidence.

Highly conformal combined radiotherapy with cisplatin and gemcitabine for treatment of loco-regionally advanced cervical cancer - a retrospective study.

BACKGROUND: Cisplatin and gemcitabine combined with conventional radiation therapy in the treatment of cervical cancer patients results in a favorable outcome but with excess toxicity. The purpose of this study was to evaluate the toxicity profile of dual chemotherapy and highly conformal external beam radiotherapy with image guided adaptive brachytherapy. METHODS: Seventeen patients with cervical carcinoma FIGO stage IB2-IIIB were treated with curative intent between 2011 and 2015. A total dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Patients with 18FDG-PET/CT positive lymph nodes (n = 15; 83.3%) received an additional boost to a total dose of 62 Gy. Chemotherapy prescription goals were: concomitant during 5 weeks of external beam radiotherapy (EBRT) 40 mg/m2 cisplatin and 125 mg/m2 gemcitabine, followed by adjuvant chemotherapy from week 10 (2 cycles 50 mg/m2 cisplatin and 1000 mg/m2 gemcitabine). EBRT was followed by 3-4 fractions (6 Gy per fraction) of intrauterine image guided adaptive brachytherapy. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: One (6%) patient developed acute grade 3 diarrhea. We did not record any other acute or late gastrointestinal or urogenital toxicity higher that grade 3. Most common acute hematological toxicity was anemia grade 2 recorded in 10 (59%) patients. There was only one case of grade 3 neutropenia (6%). The number of patients that received the complete chemotherapy regimen was gradually declining during the course of therapy. From week 2 to 5, gemcitabine was omitted in 4 (24%),7 (41%), 8 (47%), and 12 (71%) patients respectively, similarly, cisplatin was omitted in 2 (12%),3 (18%),1 (6%) and 7 (41%) patients respectively. Adjuvant chemotherapy was omitted in 8 patients (47%). During a median follow-up time of 20 months (5 to 63 months) 6 (35%) patients developed disease relapse with 5 (29%) of them in the form of systemic disease. CONCLUSIONS: In contrast to previous findings cisplatin and gemcitabine in combination with highly conformal radiation therapy seems to have an acceptable toxicity profile. Further studies are needed to determine the optimal dosage of the proposed therapy concept.

Current status and perspectives of interventional clinical trials for glioblastoma - analysis of ClinicalTrials.gov.

The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed.

Portfolio of prospective clinical trials including brachytherapy: an analysis of the ClinicalTrials.gov database.

BACKGROUND: To evaluate the current status of prospective interventional clinical trials that includes brachytherapy (BT) procedures. METHODS: The records of 175,538 (100 %) clinical trials registered at ClinicalTrials.gov were downloaded on September 2014 and a database was established. Trials using BT as an intervention were identified for further analyses. The selected trials were manually categorized according to indication(s), BT source, applied dose rate, primary sponsor type, location, protocol initiator and funding source. We analyzed trials across 8 available trial protocol elements registered within the database. RESULTS: In total 245 clinical trials were identified, 147 with BT as primary investigated treatment modality and 98 that included BT as an optional treatment component or as part of the standard treatment. Academic centers were the most frequent protocol initiators in trials where BT was the primary investigational treatment modality (p < 0.01). High dose rate (HDR) BT was the most frequently investigated type of BT dose rate (46.3 %) followed by low dose rate (LDR) (42.0 %). Prostate was the most frequently investigated tumor entity in trials with BT as the primary treatment modality (40.1 %) followed by breast cancer (17.0 %). BT was rarely the primary investigated treatment modality for cervical cancer (6.8 %). CONCLUSION: Most clinical trials using BT are predominantly in early phases, investigator-initiated and with low accrual numbers. Current investigational activities that include BT mainly focus on prostate and breast cancers. Important questions concerning the optimal usage of BT will not be answered in the near future.

Dose escalated intensity modulated radiotherapy in the treatment of cervical cancer.

PURPOSE: Standard dose of external beam radiotherapy seems to be insufficient for satisfactory control of loco-regionally advanced cervical cancer. Aim of our study is to evaluate the outcome as well as early and chronic toxicities in patients with loco-regionally advanced cervical cancer, treated with dose escalated intensity modulated radiotherapy (IMRT) combined with cisplatin chemotherapy. MATERIAL AND METHODS: Thirty-nine patients with cervical carcinoma FIGO stage IB2 - IVA were treated with curative intent between 2006 and 2010. The dose of 50.4 Gy was prescribed to the elective pelvic nodal volume. Primary tumors < 4 cm in diameter (n = 6; 15.4 %) received an external beam radiotherapy (EBRT) boost of 5.4 Gy, primary tumors > 4 cm in diameter (n = 33; 84.6 %) received an EBRT boost of 9 Gy. Patients with positive lymph nodes detected with (18)FDG-PET/CT (n = 22; 56.4 %) received a boost to a total dose of 59.4 - 64.8 Gy. The para-aortic region was included in the radiation volume in 8 (20.5 %) patients and in 5 (12.8 %) patients the para-aortic macroscopic lymph nodes received an EBRT boost. IMRT was followed with a 3D planned high dose rate intrauterine brachytherapy given to 36 (92.3 %) patients with a total dose ranging between 15-18 Gy in three fractions (single fraction: 4-6.5 Gy). Patients without contraindications (n = 31/79.5 %) received concomitantly a cisplatin-based chemotherapy (40 mg/kg) weekly. Toxicities were graded according to the common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: Mean overall survival for the entire cohort was 61.1 months (±3.5 months). Mean disease free survival was 47.2 months (±4.9 months) and loco-regional disease free survival was 55.2 months (±4.4 months). 65 % of patients developed radiotherapy associated acute toxicities grade 1, ca. 30 % developed toxicities grade 2 and just two (5.2 %) patients developed grade 3 toxicities, one acute diarrhea and one acute cystitis. 16 % of patients had chronic toxicities grade 1, 9 % grade 2 and one patient (2.6 %) toxicities grade 3 in the form of vaginal dryness. CONCLUSION: Dose escalated IMRT appears to have a satisfactory outcome with regards to mean overall survival, disease free and loco-regional disease free survival, whereas the treatment-related toxicities remain reasonably low.

Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry.

PURPOSE: Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. MATERIALS AND METHODS: The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. RESULTS: A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. CONCLUSIONS: In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.

Clinical Perspectives from Randomized Phase 3 Trials on Prostate Cancer: An Analysis of the ClinicalTrials.gov Database.

BACKGROUND: It is not easy to overview pending phase 3 trials on prostate cancer (PCa), and awareness of these trials would benefit clinicians. OBJECTIVE: To identify all phase 3 trials on PCa registered in the ClinicalTrials.gov database with pending results. DESIGN AND SETTING: On September 29, 2014, a database was established from the records for 175 538 clinical trials registered on ClinicalTrials.gov. A search of this database for the substring "prostat" identified 2951 prostate trials. Phase 3 trials accounted for 441 studies, of which 333 concerned only PCa. We selected only ongoing or completed trials with pending results, that is, for which the primary endpoint had not been published in a peer-reviewed medical journal. RESULTS AND LIMITATIONS: We identified 123 phase 3 trials with pending results. Trials were conducted predominantly in North America (n=63; 51%) and Europe (n=47; 38%). The majority were on nonmetastatic disease (n=82; 67%), with 37 (30%) on metastatic disease and four trials (3%) including both. In terms of intervention, systemic treatment was most commonly tested (n=71; 58%), followed by local treatment 34 (28%), and both systemic and local treatment (n=11; 9%), with seven (6%) trials not classifiable. The 71 trials on systemic treatment included androgen deprivation therapy (n=34; 48%), chemotherapy (n=15; 21%), immunotherapy (n=9; 13%), other systemic drugs (n=9; 13%), radiopharmaceuticals (n=2; 3%), and combinations (n=2; 3%). Local treatments tested included radiation therapy (n=27; 79%), surgery (n=5; 15%), and both (n=2; 2%). A limitation is that not every clinical trial is registered on ClinicalTrials.gov. CONCLUSION: There are many PCa phase 3 trials with pending results, most of which address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively. PATIENT SUMMARY: This report describes all phase 3 trials on prostate cancer registered in the ClinicalTrials.gov database with pending results. Most of these trials address questions regarding systemic treatments for both nonmetastatic and metastatic disease. Radiation therapy and androgen deprivation therapy are the interventions most commonly tested for local and systemic treatment, respectively.