Bisphosphonates for Osteoporosis in Nonmetastatic Prostate Cancer Patients Receiving Androgen-deprivation Therapy: A Systematic Review and Meta-analysis

This systematic review was conducted to assess the efficacy and safety of bisphosphonates for preventionand treatment of osteopenia or osteoporosis in men with non-metastatic prostate cancer receiving androgendeprivationtherapy. We searched for randomised controlled trials (RCTs) of bisphosphonates compared withplacebo from Pubmed, Embase, the Cochrane Library, and ISI - Science Citation Index. Meta-analyses of prespecifiedoutcomes (bone mineral density, fractures, and adverse events) were performed using Review Manager.Ten RCTs with a total patient population of 1,017 were identified. There was generally more improvement in bonemineral density of the lumbar spine for patients who received bisphosphonate treatment than placebo or othermedical treatment at 12 months (WMD 6.02,95%CI 5.39 to 6.65). Similar effects were also observed for totalhip, trochanter or femoral neck bone mineral density. However, there was no significant reduction in fractures.Fever and gastrointestinal symptoms were the most common adverse events (10.4% vs. 1.2%; 0.10% vs. 0.03%).Currently, our meta-analysis suggested that oral and intravenous bisphosphonates caused a rapid increasein spine and hip or femoral BMD in non-metastatic prostate cancer patients receiving androgen-deprivationtherapy. Fever and gastrointestinal symptoms were common with the use of bisphosphonates. These short-termtrials (maximum of 12 months) did not show fracture reduction. In future, more efficient performance of higherquality, more rigorous, large sample, long-term randomised controlled trials (>12 months) are needed whereoutcomes are detailed.     

Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.     

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice.It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threateninghypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules playroles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts shouldbe directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to firstskeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with nobone metastasis, and also do not prolong survival. The receptor activator for nuclear factor kB ligand inhibitordenosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides areanother treatment option for bone pain. New targeted therapies and radionuclides are still under investigation.In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.     

Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: a retrospective study

OBJECTIVE: Bone metastases are a major cause of morbidity in cancer patients. Treatment includes bisphosphonates, which are also associated with avascular osteonecrosis of the jaw (ONJ). Our aim was to evaluate the correlation between bisphosphonates and ONJ. PATIENTS AND METHODS: Of the 539 patients with bone metastases treated in our department from June 2002 to December 2006 with i.v. bisphosphonates, eight (1.5%) developed ONJ. RESULTS: The eight patients with ONJ had all been given zoledronic acid, and two had also been treated with pamidronic acid. In four of the patients, ONJ was diagnosed during treatment, while in the remaining four it was diagnosed several months after therapy with bisphosphonates had ended. Six of these patients received local noninvasive treatment, of whom five progressed. Two showed apparent autolimitation of the disease. The remaining two patients underwent surgical resection and currently show no signs of relapse. All eight ONJ patients presented with various concomitant risk factors such as paradontopathy, dental extraction, or spontaneous avulsion. CONCLUSIONS: Our results show that ONJ can appear months after interruption of treatment and that a surgical approach can be used in suitable cases. Closer cooperation is needed among specialists to define guidelines for the prevention of ONJ in patients with bone metastases.     

Time from Self-Detection of Symptoms to Seeking Definitive Care among Cervical Cancer Patients

Background: India had the burden of 97,000 new cases of cervical cancer with 60,000 deaths accounting nearly one-third of global cervical cancer deaths during the year 2018. Cervical cancer is the leading cause of cancer mortality in India. The present study aims to estimate the time interval between self-detection of cervical cancer symptoms and seeking care and different barriers for the possible time lag in seeking care. Methods: A cross-sectional study was undertaken from April 2017 to September 2017 in a regional cancer centre in the south of India. The centre has both a population and a hospital-based cancer registry. Cervical cancer cases (N= 210) with histological confirmation were interviewed at the hospital using a pre-tested semi-structured questionnaire. Results: The median time interval between the self-detection of cervical cancer symptoms and first contact with the general physician was 80 [IQR 45-150] days. The overall median time interval between the self-detection of symptoms to the initiation of primary treatment was 123[IQR 83-205] days. The major perceived reason for not seeking medical care was a lack of awareness in identifying cervical cancer symptoms in 183(92.9%) women. Conclusion: The median time of 80 days was observed from the self-detection of cervical cancer symptoms to the first contact with a general physician. Lack of awareness of patients pertaining to cancer symptoms was the major concern in seeking cancer care.     

The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy

Purpose

The aim of this study was to evaluate the efficacy and safety of zoledronic acid compared with placebo in preventing bone mineral density (BMD) loss and suppressing bone markers when initiated during the first year of androgen deprivation therapy in patients with locally advanced prostate cancer.

Patients and Methods

Patients were randomized to receive zoledronic acid 4 mg or placebo intravenously every 3 months. Lumbar spine (LS) and total hip BMD was measured using dual-energy x-ray absorptiometry at baseline and at week 52. N-telopeptide (NTX) and bone-specific alkaline phosphatase (BSAP) were evaluated at baseline and every 12 weeks. Safety assessments were performed throughout the study.

Results

Efficacy analyses included 106 patients and 109 patients in the zoledronic acid and placebo groups, respectively. At week 52, the least squares mean BMD percentage differences were 6.7% for LS and 3.7% for total hip (P < 0.0001 for both). In the zoledronic acid group, decreases in NTX (−14% to −28%) and BSAP (−31% to −37%) levels were significant and sustained; changes in NTX levels and LS BMD (r = −0.25; P = 0.04) and in BSAP levels and hip BMD (r = −0.28; P = 0.02) were significantly correlated. Only traumatic fractures were reported for 2 and 3 patients receiving zoledronic acid and placebo, respectively. One patient in each group experienced acute renal failure. Osteonecrosis of the jaw was not reported.

Conclusion

Zoledronic acid (4 mg intravenously every 3 months) was safe and effective in preventing bone loss and reducing bone turnover in patients with prostate cancer when initiated during the first year of androgen deprivation therapy; patients with low baseline BMD experienced the greatest benefit.     

Normal tissue dose and second cancer risk due to megavoltage fan-beam CT,static tomotherapy and helical tomotherapy in breast radiotherapy

This study investigates the dose from the 1 mm collimator width megavoltage fan-beam CT (fine, normal and coarse pitch) available on tomotherapy as well as for whole-breast tomotherapy treatments. The BEIR VII lifetime attributable risk model was utilised to assess the significance of the imaging dose relative to the treatment dose.     

Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second- and third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.     

Osteonecrosis of the jaw: dental outcomes in metastatic breast cancer patients treated with bisphosphonates with/without bevacizumab

The etiology, optimal management, and outcome of osteonecrosis of the jaw (ONJ) are not well understood. Because healing after mucosal trauma requires revascularization, theoretically, the combination of bevacizumab (bev) and a bisphosphonate (BP) could affect the time to development of ONJ and/or the response to dental therapy. We reviewed all cases of ONJ in metastatic breast cancer patients treated at our institution with bev+BPs and BPs alone between October 2002 and April 2010. We identified 27 ONJ patients with a median age of 57 years (range, 40 to 68 years). Seven patients received bev+BPs; 20 patients received BPs alone. Patients received intravenous zolendronate (95%), pamidronate (20%), or both (15%). Patients were treated with antibiotics (93%), alveoplasty/debridement (67%), and chlorhexidine scrub (81%). There was no difference in dental treatment between the groups or by the year of diagnosis (before 2007 versus 2007-2010). Complete resolution (CR) was achieved in 24% of all patients; 33% treated with bev+BPs, and 21% treated with BPs alone. Rates of CR improved from 15% to 33% after 2007. The median time to response was 5.6 months (range, 1.3 to 67.5 months). The addition of bev to BPs did not appear to alter the time to development of ONJ (32.6 months versus 34.6 months, respectively). The number of BP treatments administered before the diagnosis of ONJ between bev+BPs and BPs (32 doses versus 36.5 doses) was similar. However, our sample size was too small to characterize the difference statistically. Because dental management of ONJ has not changed over time at our institute, early recognition and screening may account for the improvement in dental outcomes.     

Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis

To estimate the cumulative randomized evidence for the overall incidence of bisphosphonates induced jaw osteonecrosis in adjuvant treatment of breast cancer. Systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meetings searches. We identified 15 studies reporting data on osteonecrosis of the jaw. A total of 10,694 randomized women were included, of whom 5,312 received bisphosphonates and 5,382 received either placebo or no treatment. Osteonecrosis of the jaw was a rare event, occurring in 13 (0.24%) of the 5,312 patients receiving bisphosphonates, and in one of the 5,382 patients in the control group. All the 13 events of osteonecrosis of the jaw reported among bisphosphonates arms occur in patients undergoing treatment with zoledronic acid (13/3,987, 0.33%). No events of osteonecrosis of the jaw were reported among patients randomized to receive clodronate (n = 669), pamidronate (n = 460), risedronate (n = 171), and ibandronate (n = 25); however, these samples were too small to be able to rule out the condition. Treatment with zoledronic acid was significantly associated to the occurrence of osteonecrosis of the jaw (OR = 3.23, 95% CI = 1.7–8) compared with no use. No significant between-study heterogeneity was observed. Despite use of zoledronic acid is associated to a higher number of events compared with no use, the osteonecrosis of the jaw during the adjuvant treatment of breast cancer is a rare event. At current dosage, adjuvant use of bisphosphonates in breast cancer treatment is safe. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

三尖杉酯碱及氮烯苯酸诱导肿瘤细胞凋亡的时-效,量-效关系以及凋亡与坏死的消长变化

目的:研究三尖杉酯碱及氮烯苯酸诱导肿瘤细胞凋亡的量-效,时-效关系以及凋亡与坏死的消长变化.方法:以S180腹水癌荷瘤小鼠为体内模型,HL60细胞为体外模型,以Hoechst 33342染色细胞,荧光显微镜下观察并计算凋亡指数.透射电镜判定凋亡;流式细胞仪检测DNA分布加以验证.用重复测量方差分析对凋亡指数进行量化处理;以台盼蓝染色阳性作为坏死的参数,观察凋亡与坏死的关系.结果:三尖杉酯碱和氮烯苯酸均诱导了肿瘤细胞凋亡,在荧光显微镜及透射电镜下见典型的凋亡改变.DNA直方图出现亚G1峰.对HL60细胞,在2～24小时时间范围内,三尖杉酯碱在0.02～1.0μg/ml,氮烯苯酸在0.2～5μg/ml浓度范围内,凋亡指数随药物浓度增加及时间延长而上升,24小时后,凋亡指数下降,台盼蓝染色阳性坏死细胞明显增加.在本实验的最高浓度组(三尖杉酯碱5.0μg/ml,氮烯苯酸25μg/ml)凋亡指数最低,台盼蓝阳性率一直处于最高水平.在荷S180腹水癌小鼠,氮烯苯酸在25～250mg/kg和2～48小时范围内,凋亡指数随剂量增加及时间延长而上升,48小时后,凋亡指数下降,台盼蓝染色阳性细胞明显增加.结论:三尖杉酯碱及氮烯苯酸诱导肿瘤细胞凋亡,在一定剂量和时间范围内呈现明显的量-效,时-效关系;高剂量药物倾向于以坏死为主要方式杀灭肿瘤细胞.提示细胞凋亡和坏死的启动和调控可能与损伤强度阈值和时间阈值有关.     

Aging and the cancer burden in Latin America and the Caribbean: Time to act

ObjectiveTo describe the cancer burden in adults aged 65 years and older in Latin America and the Caribbean to serve as rational for improving cancer control planning among region's older population.Materials and MethodsUsing the up-to-date GLOBOCAN estimates for 2018, we describe the cancer burden including key patterns for the major cancer sites among adults aged 65 years and older in Latin America and the Caribbean. We also predict the future burden in 2040 by applying population projections, assuming no changes in incidence rates over time.ResultsIn 2018, an estimated 679,000 new cancer cases occurred among older adults in LAC, representing almost half (48%) of the total incidence burden (43% in Central America, 49% in South America, and 52% in the Caribbean). Prostate, colorectum, and lung were the most common cancers among older males in South America and the Caribbean, with non-melanoma skin cancer ranking third in Central America. Among older females, the most common sites were breast, colorectum, and non-melanoma skin cancer, except in the Caribbean, where lung cancer ranked third. Overall, the number of new cancer cases among older adults in the region is expected to double by 2040, reaching 1.6 million new cases.ConclusionOur findings highlight the need for an urgent adaptation of healthcare systems across LAC by improving training in geriatrics for the oncology workforce, and by including older adults in clinical guidelines, insurance schemes, and cancer prevention policies.     

Burden of preventable cancers in India: Time to strike the cancer epidemic

India has a rapidly growing population inflicted with cancer diagnosis. From an estimated incidence of 1.45 million cases in 2016, the cancer incidence is expected to reach 1.75 million cases in 2020. With the limitation of facilities for cancer treatment, the only effective way to tackle the rising and humongous cancer burden is focusing on preventable cancer cases. Approximately, 70% of the Indian cancers (40% tobacco related, 20% infection related and 10% others) are caused by potentially modifiable and preventable risk factors. We review these factors with special emphasis on the Indian scenario. The results may help in designing preventive strategies for a wider application.     

Short course high fractional dose irradiation in advanced and recurrent head and neck cancer

Thirty patients with advanced head and neck cancer were treated with 400 rad daily to a total of 4400 to 5200 rad. Twenty-three patients had previously untreated stage III and IV cancer and 7 patients had recurrent head and neck cancer. As a pilot study, 9 of 30 patients also had received metronidazole (6 Mg/M²) every other day during radiotherapy.The previously untreated patients (stage III (2), stage IV (21) ) had a local control rate of 61 % (14/23) with a 45% two year actuarial survival. Three of 9 patients who were treated with high fractional dose irradiation plus metronidazole developed confluent mucositis of more than three weeks duration. Only 3 of the remaining 21 patients experienced similar mucositis. In all cases mucositis subsided without sequelae. One patient who received radiation and metronidazole and another who received radiation only developed laryngeal edema which required tracheotomy. Seven of 9 metronidazole treated patients remain disease free at this time.The 7 patients with recurrent disease achieved some degree of palliation but none survived.     

双膦酸盐和下颌骨坏死

目的:了解双膦酸盐的理化性质和药理学特性以及与其相关的下颌骨坏死的有关情况。方法:综述双膦酸盐和与其相关的下颌骨坏死的文献。结果:双膦酸盐已经被广泛用于治疗以骨吸收为特点的疾病。这些药物也越来越与下颌骨缺血性坏死这种严重的副作用联系在一起。考虑到下颌骨坏死的发生和对其缺乏有效治疗措施的事实,计划使用双膦酸盐治疗时,应认真分析风险-效益的关系,并向病人说明治疗的利弊。如果要使用双膦酸盐治疗,必须进行严谨的口腔卫生护理和定期评价口腔状况。结论:考虑到可能发生的双膦酸盐相关骨坏死的严重性,应谨慎使用这些药物并要认真观察病人。对使用这些药物治疗的病人,预防下颌骨坏死的发生尤为重要。     

双膦酸盐和下颌骨坏死

目的：了解双膦酸盐的理化性质和药理学特性以及与其相关的下颌骨坏死的有关情况。方法：综述双膦酸盐和与其相关的下颌骨坏死的文献。结果：双膦酸盐已经被广泛用于治疗以骨吸收为特点的疾病。这些药物也越来越与下颌骨缺血性坏死这种严重的副作用联系在一起。考虑到下颌骨坏死的发生和对其缺乏有效治疗措施的事实,计划使用双膦酸盐治疗时,应认真分析风险-效益的关系,并向病人说明治疗的利弊。如果要使用双膦酸盐治疗,必须进行严谨的口腔卫生护理和定期评价口腔状况。结论：考虑到可能发生的双膦酸盐相关骨坏死的严重性,应谨慎使用这些药物并要认真观察病人。对使用这些药物治疗的病人,预防下颌骨坏死的发生尤为重要。