Reversibility of castration resistance status after Radium-223 dichloride treatment: clinical evidence and review of the literature

Abstract

In the history of prostate cancer, some of the patients progressed to castration-resistant prostate cancer (CRPC) stage and, although new drugs and treatment protocols have been introduced, CRPC presents poor prognosis. This review is focused on biological mechanisms, underlying CRPC described in scientific literature in order to explain the reversion of resistance to castration. We present the case of a 73-year-old man, affected by bone metastatic CRPC, early treated with Radium-223 with a complete response. After 15 months from Radium-223 treatment, prostate-specific antigen increased with radiological progression. Androgen deprivation therapy was again performed and was effective, despite previous CRPC condition and no known mechanisms that may explain the reversion of this condition. Therefore, to our knowledge, he is the unique described case of the reversion of resistance to castration. Nevertheless, promising aspects may be lack of intrametastatic production of androgen or the suppression of bypass androgen receptor signaling pathways. Furthermore, the cytotoxic action of Radium-223 on cancer stem cell (CSC), due to surrounding clones with high-bone turnover, or the immune response that underlying the abscopal effect, may also modulate the reversion of CRPC after Radium-223. If confirmed by multicenter trials, the reversion of CRPC may impact on the management of prostate cancer.     

Introduction of the targeted alpha therapy (with Radium-223) into clinical practice in Japan: learnings and implementation

Annals of Nuclear Medicine - Radium-223 dichloride (Ra-223) is the first targeted alpha therapy approved for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone...     

Radium-223 and metastatic castration-resistant prostate cancer: All that glitters is not gold

After being approved by the National Drug Agency in several countries, Radium-223 (Ra-223) is gaining wide acceptance in the treatment of bone metastatic castration resistant prostate cancer. The exact mechanism of action remain unclear: The established model of direct alpha-particle irradiation from the remodelling bone surface, where Ra-223 accumulates, surrounding the tumor foci can explain a lethal effect only on metastatic microdeposits, but not on higher tumor burden. According to the “pre-metastatic niche model”, it is likely that Ra-223 targets several non-tumoral cell types of the tumor microenvironment involved in the complex mechanism of cancer bone homing and colonization. A deeper insight into this hypothetical mechanism will lead to a more accurate dosimetric approach and to find optimal sequencing and/or combination with the other therapeutic options.     

Impact of treatment delay in Radium-223 therapy of metastatic castration-resistant prostate cancer patients

Background

Radium-223-dichloride (Ra-223) is an alpha-emitting, bone seeking radionuclide therapy approved for patients with metastatic castration-resistant prostate cancer (mCRPC). In the fall of 2014, a global temporary shortage of Ra-223 occurred for 2 months due to production irregularities. The aim of this study was to assess whether prolonged interval between Ra-223 cycles to non-disease related causes had a negative impact on clinical outcome of therapy.

Materials and methods

Retrospective single-center study of mCRPC patients who initiated Ra-223 therapy in the period from March 2014 to February 2015. End points were number of completed Ra-223 cycles, overall survival (OS) and radiographic progression-free survival (rPFS). Bone scintigraphy, CT of thorax and abdomen, hematological status, PSA and alkaline phosphatase were evaluated prior to first dose and after 3rd and 6th treatment, respectively. Follow-up period was 18 months after first Ra-223 cycle.

Results

A total of 50 consecutive patients initiated Ra-223 therapy in the time period. Seventeen of 50 patients (34%) had prolonged interval between cycles due to delivery problems. Median delay was 4 weeks (range 3–9 weeks). Patients with delayed treatment had significantly longer median rPFS [delayed patients: 7.1 months (95% CI 4.9–9.3) vs. 4.5 months (95% CI 2.8–6.3)]. There was no significant difference in number of completed cycles or median OS.

Conclusion

We find no negative impact of prolonged interval between Ra-223 cycles due to non-disease related reasons on OS, rPFS or number of completed treatment cycles.

     

Opportunistic skeletal muscle metrics as prognostic tools in metastatic castration-resistant prostate cancer patients candidates to receive Radium-223

Annals of Nuclear Medicine - Androgen deprivation therapy alters body composition promoting a significant loss in skeletal muscle (SM) mass through inflammation and oxidative damage. We verified...     

Volumetric modulated arc therapy: a review of current literature and clinical use in practice

Volumetric modulated arc therapy (VMAT) is a novel radiation technique, which can achieve highly conformal dose distributions with improved target volume coverage and sparing of normal tissues compared with conventional radiotherapy techniques. VMAT also has the potential to offer additional advantages, such as reduced treatment delivery time compared with conventional static field intensity modulated radiotherapy (IMRT). The clinical worldwide use of VMAT is increasing significantly. Currently the majority of published data on VMAT are limited to planning and feasibility studies, although there is emerging clinical outcome data in several tumour sites. This article aims to discuss the current use of VMAT techniques in practice and review the available data from planning and clinical outcome studies in various tumour sites including prostate, pelvis (lower gastrointestinal, gynaecological), head and neck, thoracic, central nervous system, breast and other tumour sites.     

Modern dental imaging: a review of the current technology and clinical applications in dental practice

A review of modern imaging techniques commonly used in dental practice and their clinical applications is presented. The current dental examinations consist of intraoral imaging with digital indirect and direct receptors, while extraoral imaging is divided into traditional tomographic/panoramic imaging and the more recently introduced cone beam computed tomography. Applications, limitations and current trends of these dental “in-office” radiographic techniques are discussed.     

Good clinical practice, a transparent way of life. A review.

Investigators are regarded as central to the concept of clinical trials. Apart from bearing scientific responsibility, they will be confronted with a great number of ethical dilemma's concerning, amongst others, the justification and design of the trial, subject selection and informed consent, and presentation of the trial results. The ethical principles of biomedical research should be observed in accordance with a consistent moral code. The moral code of Good Clinical Practice (GCP) was developed in order to rule out inconsistencies. The principal tenets are that clinical trials should be good science, verifiable, monitored, well documented, and that they comply with the highest ethical standards. The principles of GCP are the protection of the rights of human subjects, integrity and reproducibility of data, and transparency of conduct.     

人体内镭-226含量及分布

本文分析了101例成人骨灰样品和5例成人尸解样品中镭-226和钙的含量。实验范围内,人骨中镭-226含量与年龄及骨中钙含量呈二元线性相关关系。用苏州市人口相应的年龄构成计权的人骨中镭-226含量为(5.99+0.08)×10^-4Bq／g灰。所测各部位骨的骨灰中镭-226含量的差异无显著性意义;不同部位骨的灰化率差异甚大,由尸解样品中镭-226含量估算的人体软组织中镭-226负荷量约占全身负荷量的20%。此外,本文还根据所测骨、肺、肝,胃,小肠、大肠、骨胳肌和皮肤中镭-226含量,对相应受辐射危险的组织进行了剂量估算,并估算了接受镭-226及其短寿命子体所致年剂量后随机性健康效应发生的几率,将随机性建康效应发生的几率与世界癌症发病率最低的国家或地区的相应组织或器官的癌症发病率相比较,发现前者比后者至少低约二个数量级。     

Accuracy of radiographers red dot or triage of accident and emergency radiographs in clinical practice: a systematic review

AIM: To determine the accuracy of radiographers red dot or triage of accident and emergency (A&E) radiographs in clinical practice. MATERIALS AND METHODS: Eligible studies assessed radiographers red dot or triage of A&E radiographs in clinical practice compared with a reference standard and provided accuracy data to construct 2 x 2 tables. Data were extracted on study eligibility and characteristics, quality, and accuracy. Pooled sensitivities and specificities and chi-square tests of heterogeneity were calculated. RESULT: Three red dot and five triage studies were eligible for inclusion. Radiographers' red dot of A&E radiographs in clinical practice compared with a reference standard is 0.87 [95% confidence interval (CI) 0.85-0.89] and 0.92 (0.91-0.93) sensitivity and specificity, respectively. Radiographers' triage of A&E radiographs of the skeleton is 0.90 (0.89-0.92) and 0.94 (0.93-0.94) sensitivity and specificity, respectively; and for chest and abdomen is 0.78 (0.74-0.82) and 0.91 (0.88-0.93). Radiographers' red dot of skeletal A&E radiographs without training is 0.71 (0.62-0.79) and 0.96 (0.93-0.97) sensitivity and specificity, respectively; and with training is 0.81 (0.72-0.87) and 0.95 (0.93-0.97). Pooled sensitivity and specificity for radiographers without training for the triage of skeletal A&E radiographs is 0.89 (0.88-0.91) and 0.93 (0.92-0.94); and with training is 0.91 (0.88-0.94) and 0.95 (0.93-0.96). CONCLUSION: Radiographers red dot or triage of A&E radiographs in clinical practice is affected by body area, but not by training.     

Gout: a clinical and radiologic review

Gout is a group of diseases characterized by arthritis and results from a disturbance of urate metabolism with the deposition of monosodium urate crystals in the joints and soft tissues. Often, but not invariably, the serum urate levels are elevated as a result of overproduction or underexcretion of uric acid. Clinical manifestations include acute and chronic arthritis, tophaceous deposits, interstitial renal disease, and uric acid nephrolithiasis. The diagnosis is based on the identification of uric acid crystals in joints, tissues, or body fluids. Acute episodes are treated with colchicine, NSAIDs, or steroids. Long-term management includes treatment with uricosuric agents or xanthine oxidase inhibitors.     

<Superscript>223</Superscript>Ra-Dichloride in castration-resistant metastatic prostate cancer: improving outcomes and identifying predictors of survival in clinical practice

Purpose

We first assessed whether the pattern of referrals to a nuclear medicine clinic improved as experience with ²²³Ra-dichloride increased, and whether referral patterns affected patient outcomes, and second assessed the value of bone scintigraphy, total alkaline phosphatase (tALP) and lymphadenopathy as prognostic factors in patients receiving ²²³Ra-dichloride.

Methods

A total of 57 patients eligible to receive ²²³Ra-dichloride over a 2-year period (March 2014 to March 2016) were retrospectively assessed and prospectively followed (median follow up 298 days). ²²³Ra-Dichloride was administered at 4-week intervals for a maximum of six injections. The numbers of patients in years 1 and 2 referred in relation to extent of bone disease (EOBD) category and overall survival (OS) were determined. The prognostic factors EOBD category, baseline tALP (tALP_BL), tALP response, greatest percentage reduction in tALP from baseline in any treatment cycle (ALP_max; among patients with elevated ALP_BL), and the presence of lymphadenopathy were assessed as predictors of OS.

Results

The proportion of patients with EOBD1 was higher in year 2 than in year 1 (29% and 4%, respectively), and in year 2 there was a lower rate of symptomatic skeleton-related events, a higher proportion of patients completing six cycles, and longer (albeit nonsignificant) OS (p?=?0.55). There were significant differences in OS between EOBD4 patients and those in all other groups and between EOBD1 and EOBD3 patients (p?<?0.05). OS was longer in patients with normal tALP_BL than in those with elevated tALP_BL (p?=?0.01), in ALP responders than in nonresponders (p?<?0.05), and in patients without lymphadenopathy than in those with lymphadenopathy (p?=?0.29). OS was correlated with ALP_max (r²?=?0.24).

Conclusion

A collaborative multidisciplinary referrals pathway, together with increased experience with ²²³Ra-dichloride, led to improved outcomes. In patients with elevated tALP_BL, tALP dynamics may be useful for monitoring response and predicting OS. Imaging and prognostic markers may therefore be of value for individualizing ²²³Ra-dichloride treatment and planning retreatment; however, further studies are required.

     

Colorectal carcinoma: a radiologic and clinical review

A profusion of imaging techniques is currently used for evaluating patients with suspected or known colorectal carcinoma. In most institutions, the combination of flexible sigmoidoscopy and a well-performed barium enema study should be retained as a more cost-effective, safe, and complete method of examination than colonoscopy. Endosonography appears to be promising for evaluating preoperatively the local extent of rectal carcinoma. CT is being challenged by MR imaging as the most sensitive modality for detecting liver metastases, but CT currently remains the technique of choice for evaluating recurrent disease and its extent. The diversity of available modalities will ensure that the radiologist remains at the forefront in the clinical investigation of colorectal carcinoma.     

Intensity modulated radiation therapy: a clinical review

Intensity modulated radiotherapy represents a significant advance in conformal radiotherapy. In particular, it allows the delivery of dose distributions with concave isodose profiles such that radiosensitive normal tissue close to, or even within a concavity of, a tumour may be spared from radiation injury. This article reviews the clinical application of this technique to date, and discusses the practical issues of treatment planning and delivery from the clinician's perspective.