Current Issue : July - September Volume : 2012 Issue Number : 3 Articles : 7 Articles
Patients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few\r\ntherapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease.Molecular, basic,\r\nand translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned\r\ninto a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients\r\noutside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and\r\nimmunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as\r\nnew options to treat CRPC....
Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via\r\nintraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL\r\ngene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor\r\ngrowth but cannot eliminate established lesions.We hypothesized that an underlying cause is inefficient adenoviral delivery. Using\r\nthe LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity\r\nand that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells.\r\nMany genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known\r\nas histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and\r\ninfectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that\r\nin cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi\r\nhave multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate\r\ncancer....
Objective.To examine gastrointestinal (GI) and genitourinary (GU) toxicity profiles of patients treated in 1999 with external beam\r\nradiotherapy (RT), prostate interstitial brachytherapy (PI) or radical prostatectomy (RP). Methods. TThe records of 525 patients\r\ntreated in 1999 were reviewed to evaluate toxicity. Late GI and GU morbidities were graded according to the RTOG late morbidity\r\ncriteria. Other factors examined were patient age, BMI, smoking history, and medical co-morbidities. Due to the low event rate\r\nfor late GU and GI toxicities, a competing risk regression (CRR) analysis was done with death as the competing event. Results.\r\nMedian follow-up time was 8.5 years. On CRR univariate analysis, only the presence of DM was significantly associated with GU\r\ntoxicity grade >2 (P = 0.43, HR 2.35, 95% Cl = 1.03ââ?¬â??5.39). On univariate analysis, RT and DM were significantly associated with\r\nlate GI toxicity. On multivariable analysis, both variables remained significant (RT: P = 0.038, HR = 4.71, CI = 1.09ââ?¬â??20.3; DM:\r\nP = 0.008, HR = 3.81, 95% Cl = 1.42ââ?¬â??10.2). Conclusions. Late effects occur with all treatment modalities. The presence of DM at\r\nthe time of treatment was significantly associated with worse late GI and GU toxicity. RT was significantly associated with worse\r\nlate GI toxicity compared to PI and RP....
Biochemical relapse after radical prostatectomy occurs in approximately 15ââ?¬â??40% of patients within 5 years. Postoperative radiotherapy\r\nis the only curative treatment for these patients. After radical prostatectomy, two different strategies can be offered,\r\nadjuvant or salvage radiotherapy. Adjuvant radiotherapy is defined as treatment given directly after surgery in the presence of\r\nrisk factors (R1 resection, pT3) before biochemical relapse occurs. It consists of 60ââ?¬â??64Gy and was shown to increase biochemical\r\nrelapse-free survival in three randomized controlled trials and to increase overall survival after a median followup of 12.7 years in\r\none of these trials. Salvage radiotherapy, on the other hand, is given upon biochemical relapse and is the preferred option, by many\r\ncenters as it does not include patients who might be cured by surgery alone. As described in only retrospective studies the dose\r\nfor salvage radiotherapy ranges from 64 to 72Gy and is usually dependent on the absence or presence of macroscopic recurrence.\r\nRandomized trials are currently investigating the role of adjuvant and salvage radiotherapy. Patients with biochemical relapse after\r\nprostatectomy should at the earliest sign of relapse be referred to salvage radiotherapy and should preferably be treated within a\r\nclinical trial....
The purpose of this work is to determine appropriate radiation therapy beam margins to account for intrafraction prostate\r\ntranslations for use with real-time electromagnetic position monitoring and correction strategies. Motion was measured\r\ncontinuously in 35 patients over 1157 fractions at 5 institutions. This data was studied using van Herk�s formula of (aS + ?s)\r\nfor situations ranging from no electromagnetic guidance to automated real-time corrections. Without electromagnetic guidance,\r\nmargins of over 10mm are necessary to ensure 95% dosimetric coverage while automated electromagnetic guidance allows the\r\nmargins necessary for intrafraction translations to be reduced to submillimeter levels. Factors such as prostate deformation\r\nand rotation, which are not included in this analysis, will become the dominant concerns as margins are reduced. Continuous\r\nelectromagnetic monitoring and automated correction have the potential to reduce prostate margins to 2-3mm, while ensuring\r\nthat a higher percentage of patients (99% versus 90%) receive a greater percentage (99% versus 95%) of the prescription dose....
Most advanced prostate cancers progress to castration resistant prostate cancer (CRPC) after a few years of androgen deprivation\r\ntherapy and the prognosis of patients with CRPC is poor. Although docetaxel and cabazitaxel can prolong the survival of patients\r\nwith CRPC, inevitable progression appears following those treatments. It is urgently required to identify better or alternative\r\ntherapeutic strategies. The purpose of this study was to confirm the anti-cancer activity of zoledronic acid (Zol) and determine\r\nwhether inhibition of geranylgeranylation in the mevalonate pathway could be a molecular target of prostate cancer treatment.\r\nWe examined the growth inhibitory effect of Zol in prostate cancer cells (LNCaP, PC3, DU145) and investigated a role of\r\ngeranylgeranylation in the anticancer activity of Zol.We, then, evaluated the growth inhibitory effect of geranylgeranyltransferase\r\ninhibitor (GGTI), and analyzed the synergy of GGTI and docetaxel by combination index and isobolographic analysis. Zol\r\ninhibited the growth of all prostate cancer cell lines tested in a dose-dependent manner through inhibition of geranylgeranylation.\r\nGGTI also inhibited the prostate cancer cell growth and the growth inhibitory effect was augmented by a combination with\r\ndocetaxel. Synergism between GGTI and docetaxel was observed across a broad range of concentrations. In conclusion, our results\r\ndemonstrated that GGTI can inhibit the growth of prostate cancer cells and has synergistic effect with docetaxel, suggesting its\r\npotential role in prostate cancer treatment....
Background: Several conservative (i.e., nonpharmacologic, nonsurgical) treatments exist for secondary\r\nlymphedema. The optimal treatment is unknown. We examined the effectiveness of conservative treatments for\r\nsecondary lymphedema, as well as harms related to these treatments.\r\nMethods: We searched MEDLINE�®, EMBASE�®, Cochrane Central Register of Controlled Trials�®, AMED, and CINAHL\r\nfrom 1990 to January 19, 2010. We obtained English- and non-English-language randomized controlled trials or\r\nobservational studies (with comparison groups) that reported primary effectiveness data on conservative\r\ntreatments for secondary lymphedema. For English-language studies, we extracted data in tabular form and\r\nsummarized the tables descriptively. For non-English-language studies, we summarized the results descriptively and\r\ndiscussed similarities with the English-language studies.\r\nResults: Thirty-six English-language and eight non-English-language studies were included in the review. Most of\r\nthese studies involved upper-limb lymphedema secondary to breast cancer. Despite lymphedemaâ��s chronicity,\r\nlengths of follow-up in most studies were under 6 months. Many trial reports contained inadequate descriptions of\r\nrandomization, blinding, and methods to assess harms. Most observational studies did not control for confounding.\r\nMany studies showed that active treatments reduced the size of lymphatic limbs, although extensive betweenstudy\r\nheterogeneity in areas such as treatment comparisons and protocols, and outcome measures, prevented us\r\nfrom assessing whether any one treatment was superior. This heterogeneity also precluded us from statistically\r\npooling results. Harms were rare (< 1% incidence) and mostly minor (e.g., headache, arm pain).\r\nConclusions: The literature contains no evidence to suggest the most effective treatment for secondary\r\nlymphedema. Harms are few and unlikely to cause major clinical problems....
Loading....