转移性激素敏感性前列腺癌研究进展

在过去的七十多年,转移性激素敏感性前列腺癌（mHSPC）的标准治疗一直都是单独使用雄激素剥夺治疗（ADT）。直到近几年研究显示,多西他赛（DOC）联合ADT可显著提高mHSPC患者的生存率,引起了mHSPC治疗标准的改变。近期研究证实,ADT结合醋酸阿比特龙（AA）和泼尼松（P）同样可以改善mHSPC的生存率。因此,本文将结合近期临床试验,综述mHSPC治疗的新进展。     

Race and Time to Receipt of Androgen Deprivation Therapy Among Men With Metastatic Prostate Cancer

BackgroundThe Medicare Modernization Act (MMA) drastically reduced reimbursement for androgen deprivation therapy (ADT) in 2005. One unintended consequence of the MMA may be an increase in the racial disparities in receipt of ADT. Given these policy changes, it becomes increasingly important to assess racial disparities in timely receipt of ADT.MethodsThe purpose of this study is to evaluate the associations between race and median time to receipt of ADT among men with metastatic prostate cancer before and after the passage of the MMA. A population-based retrospective cohort was created from the Surveillance, Epidemiology, and End Results-Medicare.ResultsA total of 1,846 African-American and 9,462 Caucasian men diagnosed with metastatic prostate cancer from 2000 through 2011 were included. An accelerated failure time regression model was used to examine factors associated with racial differences in median time to receipt of ADT. Results indicate that African-American men had a longer median time to receipt of ADT both before the MMA (Time Ratio (TR): 1.15; 95% Confidence Interval (CI) [1.05, 1.27]) and after the MMA (TR: 1.29; 95% CI [1.10, 1.53]) as compared to Caucasian men. In addition to race, men residing in South had longer median time to receipt of ADT (TR: 1.26, 1.52; 95% CI [1.01, 1.52; 1.24, 1.87] before and after MMA, respectively) compared to the Northeast region.ConclusionConsidering the palliative benefits of ADT, it is important to develop effective strategies to address racial differences in receipt of treatment for metastatic prostate cancer.     

Brain metastases as first manifestation of advanced cancer: exploratory analysis of 459 patients at a tertiary care center

Symptomatic brain metastases (BM) are a frequent and late complication in cancer patients. However, a subgroup of cancer patients presents with BM as the first symptom of metastatic cancer. Here we aimed to analyze the clinical course and prognostic factors of this particular BM patient population. Patients presenting with newly diagnosed BM without a history of metastatic cancer were identified from the Vienna Brain Metastasis Registry. Clinical characteristics and overall survival were retrieved by chart review. 459/2419 (19.0%) BM patients presented with BM as first symptom of advanced cancer. In 374/459 (81.5%) patients, an extracranial primary tumor, most commonly lung cancer, could be identified within 3 months after BM diagnosis. In 85/459 (18.5%) patients no extracranial primary tumor could be identified despite comprehensive diagnostic workup within the first 3 months after diagnosis of BM. Survival of patients with identified extracranial tumor differed only numerically from patients with cancer of unknown primary (CUP), however patients receiving targeted therapy after molecular workup showed significantly enhanced survival (20 months vs. 7 months; p?=?0.003; log rank test). The GPA score showed a statistically significant association with median overall survival times in the CUP BM patients (class I: 46 months; class II: 7 months; class III: 4 months; class IV: 2 months; p?<?0.001; log rank test). The GPA score has a strong prognostic value in patients with CUP BM and may be useful for patient stratification in the clinical setting. Comprehensive diagnostic workup including advanced imaging techniques and molecular tissue analyses appears to benefit patients by directing specific molecular targeted therapies.     

Castration-resistant prostate cancer: systemic therapy in 2012

Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients. Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy. Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration-resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone. Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer.     

XeNA: Capecitabine Plus Docetaxel, With or Without Trastuzumab, as Preoperative Therapy for Early Breast Cancer

Combinations of capecitabine and a taxane are highly active in metastatic breast cancer, and synergy between capecitabine and docetaxel has also been demonstrated. Such combinations potentially would provide a promising non–anthracycline-based alternative for patients with early breast cancer. Non-anthracycline preoperative regimens are a particularly interesting proposition in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as they offer less cardiotoxicity and thus can be used concomitantly with preoperative trastuzumab therapy. Capecitabine plus docetaxel (XT) and trastuzumab with XT (HXT) are promising non-anthracycline regimens for the preoperative treatment of women with HER2-negative and HER2-positive breast cancer, respectively. The Xeloda in Neoadjuvant (XeNA) trial, an open-label, multicenter, phase II study, independently assesses the efficacy of preoperative XT in HER2-negative and HXT in HER2-positive breast cancer. A particularly important feature of the XeNA study is the use of pathologic complete response (pCR) plus near pCR (npCR) as the primary endpoint. pCR is associated with long-term survival, and although it is valuable as a surrogate marker, pCR has some limitations. Measurement of residual breast cancer burden (RCB) has been proposed as a more practical alternative to predict survival after preoperative chemotherapy. The combination of RCB-0 and RCB-I (npCR) expands the subset of patients shown to benefit from preoperative chemotherapy, and achievement of pCR or npCR is associated with long disease-free survival. In XeNA, the sum of pCR and npCR will facilitate correlative studies designed to identify patients most likely to benefit from XT and HXT and may expedite the clinical evaluation of these novel preoperative regimens.     

Management of osteoporosis in men on androgen deprivation therapy

Osteoporosis is a common consequence of androgen deprivation therapy (ADT) for prostate cancer. Up to 20% of men on ADT for localized prostate cancer will fracture within 5 years. Fortunately, generally safe and effect therapy is available. Although once considered non-controversial, there is some concern about calcium supplementation, but all studies of osteoporosis therapy in men have included calcium. In most older men, serum 25-hydroxyvitamin D levels are likely to be low, although again there is controversy about the ideal level. Many experts believe that all older men, including those on ADT, need to have a level of >30 ng/ml, which is easily accomplished. Bone mineral density (BMD) testing by dual energy X-ray absorptiometry (DXA) is indicated for men on ADT. Interestingly, forearm DXA may be particularly important in ADT men, in addition to spine and hip. Some experts have suggested that men on ADT with a T-score of ≤-1.5 should be treated. Alternatively FRAX or another risk calculator can be used. Oral and intravenous bisphosphonates are FDA approved treatments for men with osteoporosis and increase BMD in men on ADT. Potential off-label agents include raloxifene and toremifene. The latter and denosumab have been shown to increase bone density and decrease vertebral fractures in men on ADT. Raloxifene and denosumab are only FDA approved for postmenopausal osteoporosis. Thus, prevention of fractures can be accomplished in this high risk population.     

Prostate Cancer Vaccines

Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising.Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.     

Prolonged survival following aggressive treatment for metastatic breast cancer in the spine

In 2007, members of our group reported a 21 month median survival for patients undergoing surgery for metastatic breast cancer in the spinal column. Cervical spine metastases were associated with decreased survival, Estrogen receptor positivity was associated with improved survival, and age and visceral metastases did not significantly impact survival. In the current study, we reassess these variables in the context of modern adjuvant therapies, and investigate the impact of the Spinal Instability Neoplastic Score (SINS). We report an observational cohort of 43 patients undergoing surgical resection for metastatic breast cancer of the spine treated at a single academic institution from June 2002 to August 2011. Patient medical records were reviewed in accordance with policies outlined by the University Institutional Review Board. Median overall survival following surgery for metastatic breast cancer in the spine was 26.8 months. 1 year overall survival was 66 %. 5 year-overall survival was 4 %. Age (p = 0.12), preoperative functional status (p = 0.17), location of metastasis (p = 0.34), the presence of visceral metastases (p = 0.68), and spinal instability (p = 0.81) were not significant variables on survival analysis. Postoperative adjuvant therapy with a single modality (radiation or chemotherapy) was associated with a significantly lower median survival compared to dual therapy with chemotherapy and radiation (p = 0.042). Patients that received radiation and chemotherapy after surgery were younger but demonstrated prolonged median survival versus single modality therapy. This data supports the concept that visceral metastases do not impact survival, however cervical spine lesions were not associated with decreased survival.     

Meeting the biologic challenge of colorectal metastases

An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90–95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20–30 % range for hepatic metastases in presence of extra hepatic disease. Such may reflect patient selection rather than a true measure of the biology of disease, and warrant clinical trial evaluation. Lastly, regional therapy and overall systemic therapy were addressed by Dr. Kemeny. The CALGB study of hepatic artery infusion (HAI) with FUDR, dexamethasone versus 5FU leucovorin showed an overall survival of 24.4 months with HAI versus 20 months with systemic therapy (P = 0.0034). An adjuvant trial of HAI at MSK in 156 patients showed an overall survival benefit at 2 year and recent long term 10yr follow-up showing a significant overall survival of 41 % with HAI versus 27 % with systemic therapy (5FU leucovorin). In the neoadjuvant Nordlinger trial for hepatic metastases, there was a significant outcome differences—the preoperative therapy group had 9.2 % increase of progression free survival versus the surgery alone group which suggests the value of combining neoadjuvant surgery in good risk liver resection candidates. Conclude the final lesson from this well presented mini symposium confirms the need for continued evaluation of the numerous discussion points by clinical trial.     

Sipuleucel-T for the treatment of metastatic prostate cancer: promise and challenges

In the past 18 mo, three new life-prolonging therapies have been approved by the US. Food and Drug Administration for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including sipuleucel-T, the first therapeutic vaccine approved for this disease. With very low toxicity and a demonstrable overall survival benefit, sipuleucel-T offers a promising new therapy and validates further investigation into other immunotherapy approaches for prostate cancer patients. However, questions about its mechanism of action, concerns about its cost, and its optimal sequencing in the prostate cancer treatment landscape may be limiting the adoption of sipuleucel-T. This review summarizes the state-of-the-science with respect to immunotherapy approaches for men with prostate cancer, provides information about the clinical development as well as the strengths and concerns associated with sipuleucel-T, and offers initial insights about where this promising treatment may best fit in the therapeutic landscape.     

The current status of checkpoint inhibitors in metastatic bladder cancer

For many decades, no significant improvements could be achieved to prolong the survival in metastatic bladder cancer. Recently, systemic immunotherapy with checkpoint inhibitors (anti-PD-L1/anti-CTLA-4) has been introduced as a novel treatment modality for patients with metastatic bladder cancer. We conducted a systematic review according to the PRISMA statement for data published on the clinical efficacy of checkpoint inhibitors in metastatic bladder cancer. Clinical efficacy of anti PD-L1 therapy was investigated in prospective trials in a total of 155 patients. Patients with positive expression for PD-L1 tended towards better overall response rates (ORR) compared to those with negative expression (34/76 vs 10/73, 45 vs 14 %; p = 0.21). Among patients with PD-L1 positive tumors, those with non-visceral metastases exhibited significantly higher ORR compared to those with visceral metastases (82 vs 28 %; p = 0.001). For anti-CTLA4 therapy, there were no data retrievable on clinical efficacy. Although data on clinical efficacy of checkpoint inhibitors in metastatic bladder cancer are currently limited, the efficacy of these drugs might depend mainly on the metastatic volume and immune system integrity. Patients with PD-L1 positive tumors and non-visceral metastases seem to derive the highest benefit from therapy.     

Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer

Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others cancers with defined cell surface markers. In summary, the approval of Sip-T based on a survival benefit and very tolerable safety profile will 1) enhance our ability to care for men with advanced prostate cancer, 2) allow for further investigations of this approach in combination with others therapies with different mechanisms of action and non-overlapping toxicities, and 3) allow further investigations earlier in the course of the disease.     

Chronic low dose ethanol induces an aggressive metastatic phenotype in TRAMP mice,which is counteracted by parthenolide

Despite advances in prostate cancer therapy, dissemination and growth of metastases results in shortened survival. Here we examined the potential anti-cancer effect of the NF-κB inhibitor parthenolide (PTL) and its water soluble analogue dimethylaminoparthenolide (DMAPT) on tumour progression and metastasis in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model of prostate cancer. Six-week-old male TRAMP mice received PTL (40 mg/kg in 10% ethanol/saline), DMAPT (100 mg/kg in sterile water), or vehicle controls by oral gavage thrice weekly until palpable tumour formation. DMAPT treatment slowed normal tumour development in TRAMP mice, extending the time-to-palpable prostate tumour by 20%. PTL did not slow overall tumour development, while the ethanol/saline vehicle used to administer PTL unexpectedly induced an aggressive metastatic tumour phenotype. Chronic ethanol/saline vehicle upregulated expression of NF-κB, MMP2, integrin β1, collagen IV, and laminin, and induced vascular basement membrane degradation in primary prostate tumours, as well as increased metastatic spread to the lung and liver. All of these changes were largely prevented by co-administration with PTL. DMAPT (in water) reduced metastasis to below that of water-control. These data suggest that DMAPT has the potential to be used as a cancer preventive and anti-metastatic therapy for prostate cancer. Although low levels of ethanol consumption have not been shown to strongly correlate with prostate cancer epidemiology, these results would support a potential effect of chronic low dose ethanol on metastasis and the TRAMP model provides a useful system in which to further explore the mechanisms involved.     

Caffeic acid phenethyl ester as an adjuvant therapy for advanced prostate cancer

Prostate cancer is the second most frequently diagnosed cancer of men. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, the majority of prostate cancer patients receiving the androgen ablation therapy will ultimately develop recurrent castration-resistant tumors within 3 years. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. Combined treatments of CAPE with chemotherapeutic drugs exhibit synergistic suppression effects. Pharmacokinetic studies suggest that intraperitoneal injection of CAPE at concentration of 10 mg/kg is not toxic. CAPE treatment sensitizes cancer cells to chemotherapy and radiation treatments. In addition, CAPE treatment protects therapy-associated toxicities in animal models. We therefore propose that administration of CAPE is a potential adjuvant therapy for patients with castration-resistant prostate cancer.     

The use of androgen deprivation therapy for prostate cancer and its effect on the subsequent dry eye disease: a population-based cohort study

This study aimed to investigate the influence of androgen deprivation therapy (ADT) for the development of dry eye disease (DED) in subjects with prostate cancer via the use of national health insurance research database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients were selected as prostate cancer with ADT according to diagnostic and procedure codes. Each participant in that group was then matched to one patient with prostate cancer but without ADT and two subject s without prostate cancer and ADT. And a total of 1791, 1791 and 3582 participants were enrolled in each group. The primary outcome was set as the DED development according to the diagnostic codes. Cox proportional hazard regression was applied to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT and other parameters for DED development. There were 228, 126 and 95 new events of DED developed in the control group, the prostate cancer without ADT group and the prostate cancer with ADT group. The rate of DED in the prostate cancer with ADT group (aHR: 0.980, 95% CI: 0.771-1.246, P= 0.8696) and Prostate cancer without ADT group (aHR: 1.064, 95% CI: 0.855-1.325, P= 0.5766) were not significantly different compared to the control group. In addition, the patients aged 70-79 years old demonstrated a significantly higher incidence of developing DED compared to those aged 50-59 years old (aHR: 1.885, 95% CI: 1.188-2.989, P= 0.0071). In conclusion, the use of ADT did not alter the incidence of subsequent DED.     

Radiotherapy versus best supportive care in patients with brain metastases and adverse prognostic factors

Several previous studies have suggested that patients with brain metastases should be treated with individualized approaches taking into account prognostic factors that influence survival. Whether or not radiotherapy represents overtreatment in patients with adverse prognostic features is currently being addressed in the randomized QUARTZ trial (best supportive care (BSC) vs. whole brain radiotherapy (WBRT)). However, inclusion is limited to patients with primary non-small cell lung cancer. Therefore, we analyzed a broader patient population with different primary tumors managed with BSC or WBRT (intended total dose 20 or 30 Gy). Survival was examined by uni- and multivariate analyses including matched pairs. Median overall survival of all 113 patients was 2 months. No significant difference between BSC and 20 Gy WBRT was observed. A slight but significant improvement was observed in the 30 Gy WBRT group (median 2.2 vs. 1.7 months). The magnitude of difference is not clinically meaningful. Subgroup analyses revealed that improved survival after 30 Gy WBRT was limited to patients with primary small cell lung cancer. In conclusion, these results confirm and extent interim results from the QUARTZ trial, suggesting that BSC is a reasonable choice in patients with limited survival expectation. Further efforts are necessary to improve identification of patients who are likely to benefit from WBRT, e.g. by refining available survival prediction tools, and to confirm that management of those with small cell lung cancer should include a less restricted use of WBRT.     

The use of collagen-based scaffolds to simulate prostate cancer bone metastases with potential for evaluating delivery of nanoparticulate gene therapeutics

Prostate cancer bone metastases are a leading cause of cancer-related death in men with current treatments offering only marginally improved rates of survival. Advances in the understanding of the genetic basis of prostate cancer provide the opportunity to develop gene-based medicines capable of treating metastatic disease. The aim of this work was to establish a 3D cell culture model of prostate cancer bone metastasis using collagen-based scaffolds, to characterise this model, and to assess the potential of the model to evaluate delivery of gene therapeutics designed to target bone metastases. Two prostate cancer cell lines (PC3 and LNCaP) were cultured in 2D standard culture and compared to 3D cell growth on three different collagen-based scaffolds (collagen and composites of collagen containing either glycosaminoglycan or nanohydroxyapatite). The 3D model was characterised for cell proliferation, viability and for matrix metalloproteinase (MMP) enzyme and Prostate Specific Antigen (PSA) secretion. Chemosensitivity to docetaxel treatment was assessed in 2D in comparison to 3D. Nanoparticles (NPs) containing siRNA formulated using a modified cyclodextrin were delivered to the cells on the scaffolds and gene silencing was quantified. Both prostate cancer cell lines actively infiltrated and proliferated on the scaffolds. Cell culture in 3D resulted in reduced levels of MMP1 and MMP9 secretion in PC3 cells. In contrast, LNCaP cells grown in 3D secreted elevated levels of PSA, particularly on the scaffold composed of collagen and glycosaminoglycans. Both cell lines grown in 3D displayed increased resistance to docetaxel treatment. The cyclodextrin.siRNA nanoparticles achieved cellular uptake and knocked down the endogenous GAPDH gene in the 3D model. In conclusion, development of a novel 3D cell culture model of prostate cancer bone metastasis has been initiated resulting, for the first time, in the successful delivery of gene therapeutics in a 3D in vitro model. Further enhancement of this model will help elucidate the pathogenesis of prostate cancer and also accelerate the design of effective therapies which can penetrate into the bone microenvironment for prostate cancer therapy.     

Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment

The role of systemic treatment was assessed after local therapy for breast cancer patients who developed central nervous system (CNS) metastases as a first and isolated recurrence. Subjects were 128 breast cancer patients with brain metastases as the first and isolated site of recurrence that were selected from 673 consecutive breast cancer patients with brain metastases treated at the same institution. Median survival from brain metastases in patients with and without systemic treatment after local therapy was respectively 15 and 4 months (p < 0.001). In patients with a Karnofsky Performance Status ≥70 and those <70, survival was respectively 16 and 5.5 months (p < 0.001). The median survival from brain metastasis in patients with solitary brain metastasis, with and without systemic treatment after local therapy, was respectively 22 and 7 months (p = 0.003). Cox multivariate analysis demonstrated that good performance status, solitary brain metastasis and systemic therapy undertaken after local treatment were factors which prolonged survival. However patient survival was adversely affected by those having leptomeningeal metastasis associated with brain parenchymal lesions. Systemic therapy, undertaken after local treatment improved survival in those patients with breast cancer and brain metastases as the site of first and isolated recurrence. Further study is required in order to fully establish the role of systemic treatment for this patient group.     

Radiotherapy in palliation of thoracic tumors: a phase I–II study (SHARON project)

The main clinical goal for patients with advanced or metastatic thoracic cancer is palliation of tumor-related symptoms and improvement of quality of life. The aim of this phase I–II trial was to define the maximum tolerated dose (MTD) of a short-course of palliative radiotherapy (RT) and to evaluate its efficacy in terms of palliative response. A phase I trial was planned with escalating dose increments. Total doses ranged from 16 to 20 Gy delivered (BID) in two consecutive days. Dose limiting toxicity was defined as any acute grade ≥?3 toxicity based on the RTOG scale. MTD was used in the phase II trial to evaluate the efficacy of this regimen using a two stage Simon’s design. Fifty-four patients were enrolled. The upper dose level of 20 Gy was defined as the MTD. In patients treated with this dose, the overall palliative response rate was 96.5% (CI 0.95: 81.3–99.9%). Complete pain relief rate was 50.0%. Median survival without symptomatic progression was 3 months. The tested short course accelerated regimen was well tolerated and effective in the palliative setting of metastatic or locally advanced chest cancer. A phase III trial is ongoing to validate this RT schedule.Trial registration: NCT03465553.     

Lung cancer with bone metastases in the United States: an analysis from the Surveillance,Epidemiologic, and End Results database

The present study used the Surveillance, Epidemiology and End Results (SEER) database to identify demographic and prognostic characteristics of lung cancer with bone metastases in the United States from 2010 to 2014. 30,364 patients with metastatic lung cancer to bones were identified in the SEER database. Their information on the basic characteristics and the histological signatures of the cancer was extracted and analyzed. Joinpoint analysis was used to test the trends in annual percentage change (APC) of the incidence. 1-year survival rate among patients with metastatic lung cancer to bones was only 20.2%, and median survival time was about 3.0 months for those patients. Young age, female sex, race other than white and black, tumor in lobes, smaller tumor, adenocarcinoma, and surgery for primary site were associated with a significant survival benefit. APC of the incidence almost increased steadily on the whole and reached the level of statistical significance among the patients older than age 60. Although there are some signatures associated with better prognosis, the overall outcome remains very poor in patients with metastatic lung cancer to bones. In addition, the incidence of lung cancer with bone metastases is increasing in certain subgroups in the United States.