Emerging therapies in metastatic bone pain

Introduction: Current treatment for metastatic bone pain is mainly palliative. Recent insights into the molecular mechanisms involved in bone metastases have led to the identification of promising therapeutic targets. This review offers an update of preclinical and clinical data on new drugs for metastatic bone pain. Areas covered: Biphosphonates are the gold standard of bone-targeted therapy in bone metastases, for their anti-resorptive and analgesic effects. New drugs aim at breaking the 'vicious cycle' of bone metastatic disease, due to the bidirectional interaction between cancer cells and bone microenvironment. Osteoprotegerin, RANK/RANKL interaction, cathepsin K, the Wnt/beta-catenin pathway and sclerostin are emerging targets for modulation of cancer-induced bone desorption. Other promising targets are those expressed in cancer cells that metastasize to bone, including Src, nerve growth factor, endothelin A, TGF-beta and CXCR4. Interesting therapeutic options include targets on nociceptors that innervate the bone, such as TPRV1, Trk and cannabinoid receptors. Expert opinion: Emerging therapies promise, in the next 10 years, a significant expansion in the array of therapeutic options for bone metastases. Most of these drugs are still in an early phase of development. Further clinical trials are needed to support the evidence of their efficacy and tolerability profile.     

Contemporary pharmacotherapy for the prevention of skeletal complications in patients with prostate cancer

Introduction: Bones represent the most common metastatic sites in prostate cancer (PCa) patients, and in addition with androgen deprivation therapy, they represent the causative reasons of bone mineral density loss and the onset of skeletal-related events.

Areas covered: An extensive search of PubMed/Medline was performed to identify randomized, Phase II/III controlled trials reporting results regarding the prevention of skeletal morbidity in patients with PCa.

Expert opinion: Preventing bone health is an imperative issue for preserving quality of life and elongate survival and, thus, a concerted effort should be made to monitor skeletal changes and to apply treatment for preventing bone loss. Although several agents have received approval for routine use, it is of paramount importance to identify the appropriate patients who would mostly be benefited by the use of these agents with attention to documenting the toxicity and economic implications. Additionally, it remains to be justified the frequency of administration in order to balance the efficacy and the potential complications.     

Emerging drugs for the treatment of bone metastasis

Introduction: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting.

Areas covered: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development.

Expert opinion: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data.     

伊班膦酸钠治疗肺癌骨转移疼痛的临床观察

目的：评价伊班膦酸钠治疗肺癌骨转移疼痛的疗效及安全性。方法：全组共26例患者，均应用伊班膦酸钠4mg稀释于0．9％氯化钠溶液或5％葡萄糖溶液500～750mL中，静脉滴注2h以上，每4周应用1次，2次后评价疗效。结果：有效率（CR＋PR）达73．1％（19／26），不良反应较轻。结论：伊班膦酸钠对肺癌骨转移引起的疼痛止痛效果强且不良反应轻，值得进一步研究。     

Efficacy and safety of ibandronate in the treatment of neoplastic bone disease

Bone is an organ commonly involved in spreading neoplastic disease, especially in multiple myeloma and carcinoma of the breast, prostate and lung. Skeletal stabilisation and pain relief are the main treatment goals in metastatic bone disease. Bisphosphonate treatment inhibits osseous breakdown and is well-established as the current standard therapy for reducing complications of neoplastic bone disease (e.g., pain, fractures and hypercalcaemia). Ibandronate is a third-generation bisphosphonate that has recently been approved for the treatment of bone metastases caused by breast cancer. The oral and intravenous formulations of ibandronate appear to have comparable efficacy. Ibandronate has also been shown to provide significant and sustained relief from metastatic bone pain over 2 years of treatment, improving patient functioning and quality of life. With a favourable long-term safety profile and the added convenience and flexibility offered by its efficacious oral formulation, ibandronate represents a new therapeutic option for metastatic bone disease management.     

Progress in the treatment of bone metastases in cancer patients

Introduction: Bone metastases are a frequent complication of cancer, occurring in up to 70% of patients with advanced breast or prostate cancer. Skeletal-related events involving pathological fractures, spinal cord compression and a need for surgery/radiotherapy, which are frequently observed in cancer patients with bone metastases have a detrimental effect on patients' survival and quality of life. Therefore, prevention of skeletal-related events is a crucial element in cancer treatment.

Areas covered: The aim of this article was to summarize data on bone-modifying agents used for treatment of cancer patients with bone metastases. We searched PubMed, EMBASE, and abstracts from ASCO, AUA, ESMO, AACR congresses for clinical studies evaluating bone-modulating agents in the treatment of patients with bone metastases.

Expert opinion: In breast cancer patients with bone metastasis, several bisphosphonates and denosumab demonstrated clinical efficacy. On the other hand, in patients with bone metastases from prostate cancer or other solid tumors only zoledronic acid and denosumab were clinically active. However, neither bisphosphonates nor denosumab have any positive impact on survival of patients with bone metastases. In a recent interim analysis of a Phase III clinical study, a novel bone-modulating agent – radium-223 chloride (alpharadin), a bone-seeking alpha emitter, has been demonstrated to significantly improve median overall survival of prostate cancer patients with bone metastases compared with placebo.     

Pharmacological management of metastatic boney pain

Many malignancies metastasise to the skeleton. This often results in a relatively unique pain process, which dramatically affects a patient’s quality of life. With one in three members of the population likely to develop cancer at some stage in their lives, the prevalence of bone metastases is high. Despite the large financial investment on therapies for these patients, treatment is still suboptimal [1]. In this article, the various treatments available are reviewed. Opiates and bisphosphonates, the mainstays in current practise, are covered in detail, and evolving therapies that may shape future management are also discussed.     

An update on first line therapies for metastatic breast cancer

Introduction: In recent years, outcomes of patients with metastatic breast cancer (MBC) have improved due to a greater understanding of the mechanisms of carcinogenesis in the development of newer molecularly targeted drugs, especially those as a front-line therapy. Remarkable improvements have been made in the treatment of hormone receptor positive (HR+) and Her2 positive MBC and currently targeted treatment strategies represent a valid first line treatment.

Areas covered: Herein, the authors provide an overview of the first-line pharmacotherapies currently available for the treatment of MBC and provide their expert perspectives on the area.

Expert opinion: Decisions on the first-line treatment of MBC should consider the clinical features of the disease, but also the biological mechanisms that regulate tumor cell growth. New and effective therapeutic agents have recently been introduced in the first-line therapy of MBC. However, to optimize the treatment of patients with metastatic disease, clinicians need biomarkers of resistance or sensitivity to targeted therapies. Efforts must also be made in developing strategies to personalize treatments of MBC patients and to identify those patients who might gain the most benefit from new treatment interventions, to save costs and limit toxicity.     

化瘀止痛联合外温法治疗转移性骨肿瘤疼痛临床观察

目的 探讨化瘀止痛联合外温法治疗转移性骨肿瘤疼痛的近期疗效.方法 将120例转移性骨肿瘤疼痛患者按照随机数字表法随机分为观察组(60例)和对照组(60例).在原有止痛基础上,观察组给予定痛膏(均匀涂覆疼痛部位,涂覆面积以超过疼痛面积2 cm为宜,厚度0.1 ～0.3 cm)联合肿瘤高频热疗治疗,对照组单用盐酸羟考酮缓释片治疗.结果 观察组部分缓解33例,轻度缓解18例,总有效率为86.4％;对照组部分缓解18例,轻度缓解26例,总有效率为73.3％;2组总有效率比较,差异有统计学意义(P＜0.05).观察组治疗后生活质量评分为(79.0±3.9)分,对照组治疗后生活质量评分为(66.0±2.0)分,2组生活质量评分比较,差异有统计学意义(P＜0.05).结论 化瘀止痛联合外温法治疗转移性骨肿瘤疼痛止痛效果明显优于单用盐酸羟考酮缓释片,并可提高生存质量.     

英卡膦酸二钠治疗恶性肿瘤骨转移疼痛15例

目的：评价注射用英卡膦酸二钠治疗恶性肿瘤骨转移疼痛的疗效和安全性。方法：共入选3l例患者，随机分为试验组15例和对照组16例。试验组用英卡膦酸二钠10mg加入生理氯化钠溶液500mL，静滴3—4h；对照组用帕米膦酸二钠90mg加入生理氯化钠溶液500mL，静滴6h。2组均单次给药后观察21d。结果：骨转移疼痛有效率试验组为66．67％(显效2例，有效8例)，对照组为75．00％(显效0例，有效12例)，2组疗效无统计学差异(P＞0．05)。2组不良反应发生率分别为18．75％和56．25％，均为I—Ⅱ度发热，经对症处理后好转。试验组不良反应发生率轮低，但2组无显著差异(P＝0．0659)。结论：英卡膦酸二钠为新一代骨吸收抑制剂，对骨转移所致疼痛有较好的止痛效果且安全。     

Sclerostin: a possible target for the management of cancer-induced bone disease

Introduction: Sclerostin is a cysteine-knot-containing protein, which is produced by osteocytes and inhibits osteoblast function. The aim of this review is to summarize the data about the role of sclerostin in cancer-induced bone disease.

Areas covered: We performed a thorough search for articles in the PubMed using the words “sclerostin, cancer, multiple myeloma”, and for similar abstracts that were presented in the ASH and ASCO annual meetings (2005 – 2011). In multiple myeloma, sclerostin is produced by myeloma cells and elevated in the serum or the plasma of the patients, and correlates with extensive bone disease and adverse myeloma features. In prostate cancer, sclerostin expression is reduced and in combination with bone morhogenetic protein-6 and noggin expression may serve as prognostic predictor for metastatic progression. In breast cancer, in vitro data suggest that the malignant cell induces the expression of sclerostin to inhibit osteoblasts in the metastatic bone area.

Expert opinion: Sclerostin may play a role in inhibiting bone formation in the biology of bone metastases in breast cancer and of myeloma-related bone disease. The results of phase I/II studies with anti-sclerostin drugs in subjects with low bone mass may lead to the potential clinical investigation of these agents in cancer-induced bone disease.     

Emerging role of Radium-223 in the growing therapeutic armamentarium of metastatic castration-resistant prostate cancer

Introduction: During the last few years, the therapeutic armamentarium of castration resistant prostate cancer (mCRPC) has been enriched with the introduction of new effective therapies with proved survival benefit and quality of life gain, including cabazitaxel, abiraterone, enzalutamide, and Radium-223.

Areas covered: Bone metastases represent a substantial cause of morbidity in mCRPC with a high rate of related skeletal events (SREs). In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-targeting radiopharmaceutical agents can provide palliation from pain. Radium-223, a calcium-mimetic, is the first α-particle emitting radiopharmaceutical that prolonged overall survival, delayed symptomatic skeletal events and improved quality of life in mCRPC.

Expert opinion: In this therapeutic scenario, no clear evidences support the best way to sequence these available agents and there is an urgent need for prospective studies to define it. 223Ra is a firmly established therapeutic option in CRPC with symptomatic bone metastases and no visceral/bulky nodal involvement, with an undeniable advantage over new hormonal agents, given its peculiar mechanism of action. Current ongoing randomized clinical trials will clarify the optimal use of this effective therapy in the therapeutic armamentarium of CRPC either alone or combined with other new approved agents and whether there is a role in patients with asymptomatic disease.     

Current and emerging systemic therapies for cutaneous metastatic melanoma

Introduction: Melanoma therapies have evolved rapidly, and initial successes have translated into survival gains for patients with advanced melanoma. Both targeted and immune-therapy now have evidence in earlier stage disease. There are many new agents and combinations of treatments in development as potential future treatment options. This highlights the need for a reflection on current treatment practice trends that are guiding the development of potential new therapies.

Areas covered: In this review, the authors discuss the evidence for currently approved therapies for cutaneous melanoma, including adjuvant therapy, potential new biomarkers, and emerging treatments with early phase clinical trial data. The authors have searched both the PubMed and clinicaltrials.gov databases for published clinical trials and discuss selected landmark trials of current therapies and of investigational treatment strategies with early evidence for the treatment of melanoma.

Expert opinion: Significant efficacy has been demonstrated with both immune checkpoint inhibitors and targeted therapies in treating advanced melanoma. A multitude of novel therapies are in development and there is need for instructive biomarker assessment to identify patients likely to respond or be refractory to current therapies, to identify mechanisms of resistance and to direct further treatment options to patients based on individual disease biology.     

Targeting glia for bone cancer pain

Introduction: Bone cancer pain (BCP) remains to be a clinical challenge with limited pharmaceutical interventions. Therefore, novel therapeutic targets for the management of BCP are in desperate need. Recently, a growing body of evidence has suggested that glial cells may play a pivotal role in the pathogenesis of BCP.

Areas covered: This review summarizes the recent progress in the understanding of glia in BCP and reveals the potential therapeutic targets in glia for BCP treatment.

Expert opinion: Pharmacological interventions inhibiting the activation of glial cells, suppressing glia-derived proinflammatory cytokines, cell surface receptors, and the intracellular signaling pathways may be beneficial for the pain management of advanced cancer patients. However, these pharmacological interventions should not disrupt the normal function of glia cells since they play a vital supportive and protective role in the central nervous system.     

Radium-223 dichloride for the treatment of castration-resistant prostate cancer with symptomatic bone metastases

Introduction: Castration-resistant prostate cancer (CRPC) is associated with the development of bone metastases, increased mortality, and a reduction in the patient’s quality of life (QOL). The management of metastatic CRPC (mCRPC) has rapidly evolved over the past decade, with a number of available therapeutic agents improving overall survival. Radium-223 dichloride (radium-223), the first targeted alpha therapy, improves survival accompanied by QOL benefits with a favorable safety profile. It is approved in over 40 countries for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease.

Areas covered: The current management of CRPC in men with bone metastases, and in particular the role of radium-223 in this setting, is reviewed and discussed. A search of bibliographic databases for peer-reviewed literature and major meetings was conducted.

Expert commentary: In treating patients with mCRPC, the best sequencing and/or combination of radium-223 with other agents has yet to be fully elucidated. The role of radium-223 in treating patients with hormone-sensitive metastatic prostate cancer who are candidates for chemotherapy should also be investigated in well-designed trials. The ability to tailor radium-223 therapy to both the clinical and genetic profiles of CRPC patients would be a promising development.     

Examination of burden of skeletal-related events in patients naive to denosumab and intravenous bisphosphonate therapy in bone metastases from solid tumors population

Objectives: Skeletal-related events (SREs), i.e. pathologic fractures, spinal cord compression, surgery and radiation to bone, are serious skeletal complications that occur frequently in patients with bone metastases (BMs) from solid tumors (STs). Clinical guidelines recommend treatment with denosumab and intravenous bisphosphonates (IVBPs) to prevent SREs. However, therapy may be delayed by physicians due to perceived low risk of SREs or for other clinical reasons. This study estimated SRE incidence rates in treatment-naive (i.e. no denosumab or IVBPs) patients with BMs from STs in the US.

Methods: In this retrospective cohort study adult patients with diagnoses of BM and ST between 1 January 2008 and 31 March 2015 were identified from MarketScan Databases. All patients had ≥6 months of data before the first BM diagnosis date (index date) and were followed for ≥6 months from the index date until the earliest of inpatient death, initiation of denosumab/IVBP therapy or end of data. The Kaplan–Meier curve was used to estimate cumulative incidence of SREs. The incremental healthcare cost of SREs was estimated and compared to propensity score matched non-SRE patients.

Results: A total of 47,052 patients met the study criteria. Using the Kaplan–Meier method the cumulative incidences of SREs among treatment-naïve patients were 39.9% (95% confidence internal [CI]: 39.4–40.4), 46.3% (95% CI: 45.8–46.8), 52.5% (95% CI: 51.9–53.2) and 59.4% (95% CI: 58.6–60.3) by month 6, 12, 24 and 48 post index date, respectively. The SRE group was associated with higher all-cause total healthcare cost per-patient-per-year compared to those without SREs ($168,277 vs. $101,020, p < .001).

Conclusions: Almost half (46.3%) of the treatment-naïve population with BMs from STs experience SREs within 1 year of the first BM diagnosis. SREs were associated with an average $67,257 additional healthcare cost annually. Given the high SRE burden in these patients, early initiation of prophylactic therapy should be considered.     

唑来膦酸注射液治疗恶性肿瘤骨转移疼痛50例

目的:评价唑来膦酸注射液治疗恶性肿瘤骨转移所致疼痛的疗效和安全性。方法:100例恶性肿瘤骨转移患者,随机分为试验组50例和对照组50例。试验组用唑来膦酸注射液4mg加入生理氯化钠溶液50mL中,静脉滴注15min;对照组用帕米膦酸二钠注射液90mg加入生理氯化钠溶液500mL中,静脉滴注6h。两组均一次性给药后观察28d。结果:治疗骨转移疼痛试验组有效率为66.6%,对照组为62.3%,两组疗效差异无显著性(P>0.05)。两组不良反应发生率分别为46.0%和44.0%,差异无显著性。两组不良反应均为Ⅰ和Ⅱ度,无需特殊处理。结论:唑来膦酸注射液治疗恶性肿瘤骨转移所引起的疼痛安全有较。     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Osseous metastases: drugs that enhance bone integrity and prevent adverse skeletal events

More than 400,000 cancer patients in the USA contend with bone metastases on an annual basis. These patients often suffer pain, a decline in quality of life, and a shortened survival. As a result, over the past several years, efforts to enhance bone integrity in patients with osseus metastases have become a major research priority. This review discusses the evolving role of bisphosphonates and their side effects, highlights other pharmacological interventions aimed at enhancing bone integrity, and reviews other pragmatic approaches to prevent worsening pain and fractures, as derived from a single institution case series of patients with problematic rib metastases.