Search

Objective TRC105 is a chimeric immunoglobulin G1 monoclonal antibody that binds endoglin ( CD105). This phase I open-label study evaluated the safety, pharmacokinetics and pharmacodynamics of TRC105 in patients with metastatic castration-resistant prostate cancer ( mCRPC). Patients and Methods Patients with mCRPC received escalating doses of i.v. TRC105 until unacceptable toxicity or disease progression, up to a predetermined dose level, using a standard 3 + 3 phase I design. Results A total of 20 patients were treated. The top dose level studied, 20 mg/kg every 2 weeks, was the maximum tolerated dose. Common adverse effects included infusion-related reaction (90%), low grade headache (67%), anaemia (48%), epistaxis (43%) and fever (43%). Ten patients had stable disease on study and eight patients had declines in prostate specific antigen (PSA). Significant plasma CD105 reduction was observed at the higher dose levels. In an exploratory analysis, vascular endothelial growth factor ( VEGF) was increased after treatment with TRC105 and VEGF levels were associated with CD105 reduction. Conclusion TRC105 was tolerated at 20 mg/kg every other week with a safety profile distinct from that of VEGF inhibitors. A significant induction of plasma VEGF was associated with CD105 reduction, suggesting anti-angiogenic activity of TRC105. An exploratory analysis showed a tentative correlation between the reduction of CD105 and a decrease in PSA velocity, suggestive of potential activity of TRC105 in the patients with mCRPC. The data from this exploratory analysis suggest that rising VEGF level is a possible compensatory mechanism for TRC105-induced anti-angiogenic activity. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? Recent advances in the treatment of metastatic castration-resistant prostate cancer ( CRPC) have resulted in improved outcomes; however, the effects have not proved to be long term, highlighting the need for new therapies, particularly in patients with docetaxel-refractory metastatic CRPC. Angiogenesis has been shown to play an important role in the development and progression of prostate cancer. Although targeting angiogenesis appears to be a rational and therapeutic approach for metastatic CRPC, identifying the appropriate subgroups that may benefit from anti-angiogenic therapy remains a challenge., The study demonstrates the potential use of dynamic contrast-enhanced ( DCE)- MRI variables as pharmacodynamic endpoints in predicting the clinical outcomes associated with anti-angiogenic agents such as cediranib. Further investigation into the potential predictive value of DCE-MRI variables as biomarkers for antiangiogenic therapy is warranted., Objective To assess the efficacy and toxicity of cediranib, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, in patients with metastatic castration-resistant prostate cancer ( CRPC) previously treated with docetaxel-based therapy., Patients and Methods The study used a Simon two-stage trial design, which required at least two of 12 patients in the first cohort to be progression-free at 6 months., We enrolled a total of 35 evaluable patients who all received cediranib 20 mg orally daily., In a second cohort, 23 additional patients received prednisone 10 mg daily with cediranib., Endpoints included tumour response, progression-free survival ( PFS), overall survival ( OS), vascular permeability via dynamic contrast-enhanced magnetic resonance imaging ( DCE-MRI), and toxicity., Results A total of 59 patients were enrolled, of whom 67% had received two or more previous chemotherapy regimens., Six of 39 patients with measurable disease had confirmed partial responses and one had an unconfirmed partial response., At 6 months, 43.9% of patients were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 months, respectively., We found that the DCE-MRI variables baseline transport constant ( Ktrans) and rate constant at day 28 were significantly associated with PFS in univariate analyses, but only baseline Ktrans remained significant when considered jointly., The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the addition of prednisone reduced the incidence of constitutional toxicities., Conclusion This study demonstrated that cediranib was generally well tolerated with some anti-tumour activity in highly pretreated patients with metastatic CRPC who had progressive disease after docetaxel-based therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, in patients with metastatic castration-resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. PATIENTS AND METHODS The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. RESULTS Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49–85) years, the on-study prostate-specific antigen level was 68.45 (5.8–995) ng/mL, the Gleason score 8 (6–9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15–48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. CONCLUSIONS Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. PATIENTS AND METHODS We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). RESULTS When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 ( P = 0.11) and D2 ( P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele ( P = 0.048). CONCLUSION A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AND METHODS In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment ( p = 0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype ( P = 0.013). CONCLUSION Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC. [ABSTRACT FROM AUTHOR]

OBJECTIVE To identify patients with androgen-independent prostate cancer (AIPC) with bone metastasis and no soft-tissue metastases at the time of protocol enrolment, and analyse their disease progression by computed tomography (CT), bone scan, and prostate-specific antigen (PSA) level to determine the utility of routine interval CT in such patients. PATIENTS AND METHODS Bone is the most common metastatic site in patients with AIPC and the only site of metastatic disease for many; because some with initial bone metastasis eventually develop soft-tissue disease, many clinical trials use routine CT to monitor for the latter as a sign of disease progression, but the actual incidence of new soft-tissue metastases is unknown and the role of routine interval CT in monitoring for disease progression, especially for asymptomatic patients, is unclear. Thus we reviewed 175 cases of metastatic AIPC from three randomized phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) at the National Cancer Institute between 1995 and 2004. The patients’ PSA levels were assessed every 4 weeks, and CT and bone scans were done every 2–3 months. We retrospectively identified patients with bone metastasis only and examined subsequent CT for the occurrence of soft-tissue disease. For patients with progressive disease, we also examined bone scan and PSA progression. RESULTS Of 175 patients with metastatic prostate cancer, 105 (60%) had bone metastasis only, 12 (6.9%) had soft-tissue metastases only, and 58 (33.1%) had both bone and soft-tissue metastases. The median (range) follow-up was 8 (1–44) months for the 105 patients with bone metastasis only. During that time, two patients (1.9%) developed new soft-tissue disease; one developed right iliac fossa lymphadenopathy after 8 months and the other developed a perirectal mass after 12 months. The patient with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The patient with the perirectal mass had PSA progression and a palpable abnormality. CONCLUSION This review of patients with AIPC and bone metastasis only, followed for a median of 8 months on clinical trials, shows that the incidence of asymptomatic new soft-tissue disease as the only sign of disease progression is quite low. Therefore, routine CT to exclude new soft-tissue disease in this population appears to be unwarranted. We recommend that for these patients CT is done only at the time of disease progression, as shown by bone scan, PSA level, or clinical presentation. We do not exclude the possibility that patients who remain on trial for significantly longer periods might benefit from routine interval CT. [ABSTRACT FROM AUTHOR]

Authors from the National Cancer Institute present a study which assessed the time to androgen independence and overall survival for patients with metastatic prostate cancer. They reported a longer than expected survival with androgen-independent prostate cancer, and make original observations on the time to metastatic disease for patients with no evidence of radiographic disease. The new wave of chemotherapeutic agents for hormone-resistant prostate cancer has generated a new interest in producing more. Dr Cora Sternberg from Rome presents information on satraplatin, a third-generation orally available platinum analogue that shares more structural similarities with cisplatin. There are several other papers in this section on prostate bladder and renal cancer, and finally a paper from London on penile cancer, asking what surgical resection margins are required to achieve oncological control, and finding that the traditional 2 cm margin may be unnecessary, with excision margins of only a few millimetres needed to give excellent control. OBJECTIVE To determine the natural history of patients with prostate cancer who start initial androgen-deprivation therapy (ADT) for biochemical failure with no radiographic evidence of disease (D0) or with radiographic metastatic disease (D2), as the history is either not well-defined or is changing, and such data are critical for guiding therapy after prostate cancer recurrence. PATIENTS AND METHODS We retrospectively assessed the time to androgen-independence (AI), defined as the first sustained rise in prostate-specific antigen (PSA) level on ADT, time to metastatic disease and overall survival for 80 patients with metastatic prostate cancer in clinical trials at the National Cancer Institute. RESULTS ADT was initiated after metastatic disease in 37 patients and before metastatic disease in 43 patients; in these 43 patients, the median time to developing metastatic disease on ADT was 37.8 months. The median time to AI from the initiation of ADT was 19.3 and 13.1 months in D0 and D2 patients, respectively. The median overall survival from the start of ADT was 89.0 and 63.0 months, and the median overall survival from the time of AI was 63.1 and 44.2 months in D0 and D2 patients, respectively. These 80 patients, which included 43 who had no metastatic disease when starting ADT, had a median survival of 54.8 months after AI prostate cancer. CONCLUSIONS We describe the natural history of AI prostate cancer in D0 patients who eventually developed metastasis, and in D2 patients. The results suggest a longer than expected survival with AI prostate cancer, and to our knowledge this is the first study to report the time to metastatic disease for D0 patients from ADT and from AI. These results can be used to help design clinical trials in patients with D0 prostate cancer. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the role of the iron-regulatory hormone hepcidin in the development of anaemia in men afflicted with prostate cancer.