Elmar Heinrich

Cabazitaxel Plus Prednisone for Metastatic Castration-resistant Prostate Cancer Progressing After Docetaxel: Results from the German Compassionate-use Programme

BACKGROUND Cabazitaxel (Cbz) is an approved second-line treatment in metastatic castration-resistant prostate cancer (mCRPC) following docetaxel therapy with a significant survival benefit compared with mitoxantrone. However, grade 3/4 toxicities were reported in 82% of patients. OBJECTIVE To report on the safety results of mCRPC patients treated within a compassionate-use programme in Germany. DESIGN, SETTING, AND PARTICIPANTS A total of 111 patients with a mean age of 67.9 yr (range: 49-81 yr) and progressive mCRPC were included. Patients had received a mean number of 12.7 ± 10.8 cycles (range: 6-69 cycles) of docetaxel with a mean cumulative dose of 970.9 mg/m(2); mean time from last docetaxel application to progression was 6.95 mo (range: 2-54 mo). Of the patients, 31.5% progressed by prostate-specific antigen (PSA) increase only; the remainder had a combination of PSA increase and clinical progression. INTERVENTION Cbz at a dosage of 25mg/m(2) intravenously every 3 wk combined with 5mg of oral prednisone twice a day. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Treatment-associated toxicity was the primary study end point; progression-free and overall survival were secondary end points. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS Patients received a mean number of 6.5 ± 2.2 cycles of Cbz and a mean cumulative dose of 160.3 ± 51.5mg/m(2). Grade 3 and 4 treatment-emergent adverse events were recorded in 34 patients (30.6%) and 18 patients (16.2%), respectively. Grade 3/4 anaemia, neutropenia, and thrombocytopenia were reported in 4.5%, 7.2%, and 0.9% of the patients, respectively. Neutropenic fever was reported in 1.8% of the patients. Grade 3/4 gastrointestinal toxicity was identified in 4.5% of the patients. Three patients died because of Cbz-related toxicity. Granulocyte colony-stimulating growth factors were used in 17.1% of patients. The limitations are due to the nonrandomised nature of the trial. CONCLUSIONS Treatment with Cbz is tolerable and is associated with a low incidence of serious adverse events in a real-world patient population with CRPC. The outcome of serious adverse events can be minimised with proactive treatment management and conscientious monitoring.

120 W Lithium Triborate Laser for Photoselective Vaporization of the Prostate: Comparison with 80 W Potassium-Titanyl-Phosphate Laser in an Ex-Vivo Model

PURPOSE To evaluate the ablative and hemostatic properties of the recently introduced 120 W lithium triborate (LBO) 532 nm laser and compare the results against the conventional 80 W potassium-titanyl-phosphate (KTP) laser. MATERIALS AND METHODS The ex-vivo model of the isolated blood-perfused porcine kidney was used to determine the ablation capacity, hemostatic properties, and coagulation depth of the GreenLight HPS laser system (American Medical System, Minnetonka, MN) that used an output power of 120 W. The results were compared with the KTP laser that used output power levels of 30 W, 50 W, and 80 W. Unperfused kidneys were weighed before and after 10 minutes of laser ablation in an area of 3 x 3 cm; the weight difference marked the amount of removed tissue. Bleeding was determined by the weight difference of a swab before and after it was placed on the bleeding surface for 60 seconds after ablating a surface area of 9 cm(2) on blood-perfused kidneys. RESULTS With a tissue removal of 7.01 +/- 1.83 g after 10 minutes of laser ablation at 120 W, the LBO laser offered a significantly higher ablation capacity compared with 3.99 +/- 0.48 g reached with the conventional KTP laser at 80 W in the same time interval (P < 0.05). The bleeding rate was also significantly increased using the LBO at 120 W compared with the conventional device at 80 W (0.65 +/- 0.26 g/min vs 0.21 +/- 0.07 g/min; P < 0.05). The corresponding depths of the coagulation zones were 835 +/- 73 microm and 667 +/- 64 microm (P < 0.05), respectively. CONCLUSION The 120 W LBO laser offers a significantly higher tissue ablation capacity compared with the conventional 80 W KTP laser. Because the increased efficacy of the device is accompanied by a higher bleeding rate and a slightly deeper coagulation zone, the user has to select the appropriate output power levels carefully for a safe and efficient treatment. Nevertheless, the bleeding rate compared with previous studies of transurethral resection of the prostate is significantly reduced.

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

The aim of this study was to investigate the effect of treatment of experimental ovarian cancers with targeted cytotoxic analogs as single compounds and in combination. Targeted cytotoxic analogs of bombesin (AN-215), somatostatin (AN-238), and luteinizing hormone-releasing hormone (AN-207) consisted of 2-pyrrolinodoxorubicin (AN-201) linked to the respective peptide carrier. AN-238 at 200 nmol/kg significantly inhibited growth of UCI-107, ES-2 and OV-1063 ovarian cancers. AN-215 alone at 200 nmol/kg and its combination with AN-238 at one-half of the dose were also able to inhibit the growth of UCI-107 tumors. A combination of AN-238 with AN-207at 50% of the dose strongly suppressed the proliferation of ES-2 and OV-1063 ovarian tumors. Cytotoxic radical AN-201 was toxic and had no significant effect on tumor growth. In contrast, the toxicity of the conjugated peptide analogs was low. Because ovarian cancers tend to acquire chemoresistance, we used real-time PCR to measure the mRNA expression of multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein after treatment. Low or no induction of multidrug resistance protein 1, multidrug resistance-related protein, and breast cancer resistance protein occurred after treatment with AN-238, AN-215, and the combination of AN-238 with AN-207 or AN-215. These results demonstrate that a therapy with cytotoxic analogs such as single agents and combinations is effective and nontoxic. Our work suggests that cytotoxic peptide analogs of luteinizing hormone-releasing hormone, somatostatin, and bombesin could be used for the therapy of ovarian cancers, considering the lack of induction of chemoresistance.

Potentiation of mammary cancer inhibition by combination of antagonists of growth hormone-releasing hormone with docetaxel

Antagonists of growth hormone-releasing hormone (GHRH) are being developed for the treatment of various cancers. In this study, we investigated the effectiveness of treatment with GHRH antagonist JMR-132 alone and in combination with docetaxel chemotherapy in nude mice bearing MX-1 human breast cancers. Specific high-affinity binding sites for GHRH were found on MX-1 tumor membranes using ligand competition assays with 125I-labeled GHRH antagonist JV-1-42. JMR-132 displaced radiolabeled JV-1-42 with an IC50 of 0.14 nM, indicating a high affinity of JMR-132 to GHRH receptors. Treatment of nude mice bearing xenografts of MX-1 with JMR-132 at 10 μg per day s.c. for 22 days significantly (P < 0.05) inhibited tumor volume by 62.9% and tumor weight by 47.8%. Docetaxel given twice at a dose of 20 mg/kg i.p. significantly reduced tumor volume and weight by 74.1% and 58.6%, respectively. Combination treatment with JMR-132 (10 μg/day) and docetaxel (20 mg/kg i.p.) led to growth arrest of most tumors as shown by an inhibition of tumor volume and weight by 97.7% and 95.6%, respectively (P < 0.001). Because no vital cancer cells were detected in some of the excised tumors, a total regression of the tumors was achieved in some cases. Treatment with JMR-132 also strongly reduced the concentration of EGF receptors in MX-1 tumors. Our results demonstrate that GHRH antagonists might provide a therapy for breast cancer and could be combined with docetaxel chemotherapy to enhance the efficacy of treatment.

Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel

We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice. Treatment with MZ-J-7-138 or JV-1-92 inhibited orthotopic growth of H460 NSCLC by 52–65% (P < 0.001) and was associated with a significant decrease in protein expression of K-Ras, cyclooxygenase-2 (Cox-2) and phospho-Akt (pAkt). In other experiments, treatment with MZ-J-7-138 or docetaxel reduced tumor volume of s.c. xenografted H460 human NSCLC by 30–36% (P < 0.01). The combination of MZ-J-7-138 and docetaxel resulted in a synergistic growth inhibition of H460 NSCLC xenografts of 63%. MZ-J-7-138 alone or in combination with docetaxel significantly reduced protein levels of K-Ras, Cox-2, and pAkt by 56–63%. Docetaxel given singly diminished the protein levels only of Cox-2 and did not affect K-Ras and pAkt. High-affinity binding sites, mRNA, and protein expression of pituitary GHRH receptors and its splice variant (SV) 1 were found in H460. H460 NSCLC cells contained GHRH peptide, and its growth was significantly inhibited in vitro by 10 μM MZ-J-7-138 (P < 0.001). Serum insulin-like growth factor 1 (IGF1) was not reduced by either GHRH antagonists. These findings suggest that antiproliferative effects of GHRH antagonists in H460 NSCLC are associated with down-regulation of K-Ras, Cox-2, and pAkt. In conclusion, GHRH antagonists in combination with docetaxel synergistically inhibit growth of H460 NSCLC and the expression of K-ras, Cox-2, and pAkt, which might abrogate the signal transduction pathways for cell growth stimulation and therapeutic resistance.

Dose-dependent growth inhibition in vivo of PC-3 prostate cancer with a reduction in tumoral growth factors after therapy with GHRH antagonist MZ-J-7-138.

Antagonists of growth hormone‐releasing hormone (GHRH) inhibit the growth of various cancers and affect tumoral growth factors.

Neuroendocrine tumor cells in prostate cancer: Evaluation of the neurosecretory products serotonin, bombesin, and gastrin – impact on angiogenesis and clinical follow-up

Neuroendocrine differentiated tumor cells (NETC) can be found in a large portion of prostate carcinoma (PCa) specimens. This is the first study to systematically quantify and analyze the influence of the NETC distribution and of their secretory products, serotonin, bombesin, and gastrin, on angiogenesis and in the clinical follow‐up of PCa patients.

Clinical impact of intraoperative frozen sections during nerve-sparing radical prostatectomy

PurposeEnhanced surgical techniques and standardised selection criteria have led to a higher rate of nerve-sparing (NS) radical prostatectomy (RP) procedures. The aim of this study was to evaluate the clinical value of intraoperative frozen sections (IFS) during nerve-sparing radical prostatectomy (NSRP).Materials and methodsThousand and eighty-three patients with localised prostatic carcinoma were treated using retropubic RP (from 2004 to 2006). Two hundred and eighty-seven of the 1083 documented cases received NS. One hundred and thirty procedures were carried out with IFS from the area of the neurovascular bundles and 157 without IFS. The decision to use IFS was made intraoperatively and based on clinical suspicion of possible positive resection margins in the area of the bundles.ResultsIn the NS group with IFS, the results revealed positive margins in nine (6.9%) out of 130 cases, resulting in subsequent resection of the ipsilateral neurovascular bundle. The final histological report on this group revealed four additional patients (3.1%) with positive margins, but only one (0.7%) in the area of the previous neurovascular bundle. The final histopathologic reports on the 157 NS cases without IFS showed that the positive margin was in the area of the previous neurovascular bundle in only one (0.6%) of the nine cases with positive margins (5.7%).ConclusionAccording to our data, there is no need for routine IFS during NSRP. The negative predictive value for infiltration of the NVB is high, and IFS can be dispensed with. Intraoperative biopsies should be taken in those cases where the surgeon is in doubt about the resection margins in the area of bundles.

Radical Prostatectomy After Previous Transurethral Resection of the Prostate: Robot-Assisted Laparoscopic Versus Open Radical Prostatectomy in a Matched-Pair Analysis

PURPOSE To determine whether previous transurethral resection of the prostate (TURP) compromises the surgical outcome and pathologic findings in patient who underwent either radical robot-assisted laparoscopic prostatectomy (RALP) or open retropubic radical prostatectomy (RRP) after TURP, because TURP is reported to complicate radical prostatectomy and there are conflicting data. PATIENTS AND METHODS From July 2008 to July 2010, 357 patients underwent RALP. Of these, 19 (5.3%) patients had undergone previous TURP. Operative and perioperative data of patients were compared with those of matched controls selected from a database of 616 post-RRP patients. Matching criteria were age, clinical stage, the level of preoperative prostate-specific-antigen, the biopsy Gleason score, the American Society of Anesthesiologists classification score, and prostate volume assessed during transrectal ultrasonography. All RRP and RALP procedures were performed by experienced surgeons. RESULTS Mean time to prostatectomy was 67.4 months in the RALP group and 53.1 months in the RRP group. Mean operative time was 217 ± 51.9 minutes for RALP and 174 ± 57.7 minutes for RRP (P<0.05). The overall positive surgical margin rate was 15.8% in both groups (pT(2) tumors: 10.5% for RALP and 5.3% for RRP; P=1.0). Mean estimated blood loss was 333 ± 144 mL in RALP patients and 1103 ± 636 mL in RRP patients (P<0.001). The difference between preoperative and postoperative hemoglobin levels was 3.22 ± 0.98 g/dL for RALP and 5.85 ± 1.95 g/dL for RRP (P=0.0002). The RALP and RRP groups also differed in terms of hospital stay (8.58 ± 1.17 vs 11.74 ± 5.22 days; P=0.0037), duration of catheterization (7.95 ± 5.69 vs 11.78 ± 6.97 days; P=0.0016), postoperative complications according to the Clavien classification system (6 vs 15 patients; P=0.0027), and transfusion rate (0% vs 10.5%; P<0.001). CONCLUSION RALP offers advantages over open radical prostatectomy after previous surgery. Although both techniques are associated with adequate surgical outcomes, RALP appeared to be preferable in our population of patients with previous prostate surgery.

Influence of abiraterone acetate on circulating neuromediators in chemotherapy-naïve castration-resistant prostate cancer

Abiraterone Acetate (AA) represents a highly effective androgen‐receptor (AR) axis targeted agent. Treatment with AA in castration‐resistant prostate cancer (CRPC) may partly mediate neuroendocrine differentiation (NED) as an escape mechanism, which may have implications for the choice of sequential therapy in CRPC. We evaluated how treatment with AA influences circulating neuromediators chromogranin A (CGA), neuron‐specific enolase (NSE), and pro‐gastrin‐releasing peptide (Pro‐GRP) in chemotherapy‐naïve CRPC patients.