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The Cochrane Database of Systematic... Oct 2017Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast-mediated bone resorption, and novel targeted therapies such as denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012.
OBJECTIVES
To assess the effects of bisphosphonates and other bone agents in addition to anti-cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM).
SEARCH METHODS
In this review update, we searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 19 September 2016.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone-acting agent with the same treatment without a bisphosphonate/bone-acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone-acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone-acting agent versus delayed treatment of the same bisphosphonate/bone-acting agent.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal-related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta-analyses used random-effects models. Secondary outcomes included overall survival and disease-free survival for EBC; we derived hazard ratios (HRs) for these time-to-event outcomes where possible. We collected toxicity and quality-of-life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting.
MAIN RESULTS
We included 44 RCTs involving 37,302 women.In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate-quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time-to-event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high-quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high-quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high-quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease-free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high-quality evidence with significant heterogeneity present) however subgroup analyses showed a disease-free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high-quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate-quality evidence due to wide confidence intervals). We await mature overall survival and disease-free survival results for denosumab trials.In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate-quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high-quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low-quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate-quality evidence).In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high-quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high-quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate-quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate-quality evidence with significant heterogeneity). Quality-of-life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate-quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high-quality evidence).
AUTHORS' CONCLUSIONS
For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease-free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.
Topics: Administration, Oral; Bone Density Conservation Agents; Bone Neoplasms; Breast Neoplasms; Clodronic Acid; Denosumab; Diphosphonates; Female; Humans; Imidazoles; Injections, Intravenous; Randomized Controlled Trials as Topic; Zoledronic Acid
PubMed: 29082518
DOI: 10.1002/14651858.CD003474.pub4 -
Journal of Orthopaedic Surgery and... Jun 2021To compare the efficacy and safety between denosumab and zoledronic acid for advanced cancer with bone metastasis. (Meta-Analysis)
Meta-Analysis
Comparison of denosumab and zoledronic acid for the treatment of solid tumors and multiple myeloma with bone metastasis: a systematic review and meta-analysis based on randomized controlled trials.
OBJECTIVE
To compare the efficacy and safety between denosumab and zoledronic acid for advanced cancer with bone metastasis.
METHODS
MEDLINE, EMBASE, and the Cochrane library databases were searched for randomized controlled trials up to December 2020 that compared denosumab and zoledronic acid in the treatment of advanced cancer with bone metastasis. The following clinical outcomes were extracted for analysis: time to first skeletal-related event, time to first-and-subsequent skeletal-related events, overall survival, and disease progression. Safety outcomes including incidence of adverse events, serious adverse events, acute-phase reactions, renal toxicity, osteonecrosis of the jaw, and hypocalcemia were also extracted.
RESULTS
Four randomized controlled trials involving 7201 patients were included. The overall analysis showed that denosumab was superior to zoledronic acid in delaying time to first skeletal-related event (hazard ratio = 0.86; 95% confidence interval, 0.80-0.93; P < 0.01) and time to first-and-subsequent skeletal-related events (risk ratio 0.87; 95% confidence interval 0.81-0.93; P < 0.01). Denosumab was associated with lower incidence of renal toxicity (risk ratio 0.69; 95% confidence interval 0.54-0.87; P < 0.01) and acute phase reaction (risk ratio 0.47; 95% confidence interval 0.38-0.56; P < 0.01), but higher incidence of hypocalcemia (risk ratio 1.78; 95% confidence interval 1.33-2.38; P < 0.01) and osteonecrosis of the jaw (risk ratio 1.41; 95% confidence interval 1.01-1.95; P = 0.04). No significant differences were found in overall survival, time to disease progression, or incidence of adverse events and serious adverse events between denosumab and zoledronic acid.
CONCLUSIONS
Compared with zoledronic acid, denosumab is associated with delayed first-and-subsequent skeletal-related events, lower incidence of renal toxicity, and acute phase reaction, but higher incidence of hypocalcemia and osteonecrosis of the jaw. Hence, denosumab seems to be a promising choice for advanced cancer with bone metastasis. Nonetheless, more randomized controlled trials are needed for further evaluation.
Topics: Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Humans; Multiple Myeloma; Plasmacytoma; Randomized Controlled Trials as Topic; Treatment Outcome; Zoledronic Acid
PubMed: 34158101
DOI: 10.1186/s13018-021-02554-8 -
Cancer Reports (Hoboken, N.J.) Dec 2021Management of the node-negative neck in oral maxillary squamous cell carcinoma (SCC), encompassing the hard palate and upper alveolar subsites of the oral cavity, is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Management of the node-negative neck in oral maxillary squamous cell carcinoma (SCC), encompassing the hard palate and upper alveolar subsites of the oral cavity, is controversial, with no clear international consensus or recommendation regarding elective neck dissection in the absence of cervical metastases.
AIM
To assess the occult metastatic rate in patients with clinically node negative oral maxillary SCC; both as an overall metastatic rate, and a comparison of patients managed with an elective neck dissection at index surgery, compared to excision of the primary with clinical observation of the neck.
METHODS AND RESULTS
A systematic review was performed by two independent investigators for studies relating to oral maxillary SCC and analysed according to PRISMA criteria. Data were extracted from Pubmed, Ovid MEDLINE, EMBASE, and SCOPUS via relevant MeSH terms. Grey literature was searched through Google Scholar and OpenGrey. Five hundred and fifty-three articles were identified on the initial search, 483 unique articles underwent screening against eligibility criteria, and 29 studies were identified for final data extraction. Incidence of occult metastases in patients with clinically node negative oral maxillary SCC was identified either on primary elective neck dissection or on routine follow up. Meta-analyses were performed. Of 553 relevant articles identified on initial search, 29 were included for analysis. The pooled overall rate of occult metastases in patients initially presenting with clinically node-negative disease was 22.2%. There is a statistically significant effect of END on decreasing regional recurrence demonstrated in this study (RR 0.36, 95% CI 0.24, 0.59).
CONCLUSION
The results of this systematic review and meta-analysis suggest elective neck dissection for patients presenting with hard palate or upper alveolar SCC, even in a clinically node negative neck.
Topics: Animals; Head and Neck Neoplasms; Humans; Lymphatic Metastasis; Maxillary Neoplasms; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck
PubMed: 33963809
DOI: 10.1002/cnr2.1410 -
Journal of Oral Pathology & Medicine :... Aug 2022To investigate and compare the demographic data, occurrence of recurrence and metastasis, and survival prognosis between ameloblastic carcinoma (AC) and metastasizing... (Review)
Review
PURPOSE
To investigate and compare the demographic data, occurrence of recurrence and metastasis, and survival prognosis between ameloblastic carcinoma (AC) and metastasizing ameloblastoma (MA), based on appropriate and currently accepted eligible diagnostic criteria, in a systematic review of the literature.
METHODS
An electronic search was undertaken, last updated in December 2021. Eligibility criteria included publications having enough clinicopathological information to confirm the diagnosis of these tumors.
RESULTS
Seventy-seven publications reporting 85 ACs and 43 MAs were included. Both tumors were more frequent in mandible and showed different clinical profiles regarding patients' sex and age. There was no difference in the estimated cumulative survival between patients diagnosed with these tumors. Metastases mainly affected the lungs, followed by cervical lymph nodes. The mean time between the first metastasis and the last follow-up was higher for MA (p = 0.021). In addition, MA patients remained alive longer than AC patients after the first metastasis diagnosis (p = 0.041). Considering only the cases that metastasized, a higher ratio of AC patients died in comparison to MA patients (p = 0.003). The occurrence of recurrence was associated with a conservative primary treatment with both AC (p < 0.001) and MA tumors (p = 0.017). Multiple recurrent events were associated with conservative primary therapies with MA (p < 0.001) but not with AC (p = 0.121).
CONCLUSION
In addition to some demographic differences, ACs that metastasize present a worse prognosis than MA. As conservative procedures are associated with multiple recurrent events, this treatment modality should be avoided for both tumors.
Topics: Ameloblastoma; Carcinoma; Humans; Mandible; Mandibular Neoplasms; Odontogenic Tumors
PubMed: 35822408
DOI: 10.1111/jop.13334 -
Annals of Internal Medicine Nov 2014Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it. (Review)
Review
BACKGROUND
Osteoporosis is a major contributor to the propensity to fracture among older adults, and various pharmaceuticals are available to treat it.
PURPOSE
To update a review about the benefits and harms of pharmacologic treatments used to prevent fractures in adults at risk.
DATA SOURCES
Multiple computerized databases were searched between 2 January 2005 and 4 March 2014 for English-language studies.
STUDY SELECTION
Trials, observational studies, and systematic reviews.
DATA EXTRACTION
Duplicate extraction and assessment of data about study characteristics, outcomes, and quality.
DATA SYNTHESIS
From more than 52 000 titles screened, 315 articles were included in this update. There is high-strength evidence that bisphosphonates, denosumab, and teriparatide reduce fractures compared with placebo, with relative risk reductions from 0.40 to 0.60 for vertebral fractures and 0.60 to 0.80 for nonvertebral fractures. Raloxifene has been shown in placebo-controlled trials to reduce only vertebral fractures. Since 2007, there is a newly recognized adverse event of bisphosphonate use: atypical subtrochanteric femur fracture. Gastrointestinal side effects, hot flashes, thromboembolic events, and infections vary among drugs.
LIMITATIONS
Few studies have directly compared drugs used to treat osteoporosis. Data in men are very sparse. Costs were not assessed.
CONCLUSION
Good-quality evidence supports that several medications for bone density in osteoporotic range and/or preexisting hip or vertebral fracture reduce fracture risk. Side effects vary among drugs, and the comparative effectiveness of the drugs is unclear.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality and RAND Corporation.
Topics: Absorptiometry, Photon; Adult; Antibodies, Monoclonal, Humanized; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density; Bone Density Conservation Agents; Comparative Effectiveness Research; Denosumab; Female; Fractures, Bone; Humans; Male; Neoplasms; Osteoporosis; Osteoporotic Fractures; Teriparatide
PubMed: 25199883
DOI: 10.7326/M14-0317 -
Brazilian Dental Journal 2017Here is described a case of ameloblastic fibrosarcoma (AFS) affecting the posterior mandible of a woman who was treated surgically and recovered without signs of... (Review)
Review
Here is described a case of ameloblastic fibrosarcoma (AFS) affecting the posterior mandible of a woman who was treated surgically and recovered without signs of recurrence or metastasis after 12 years of follow-up. Tumor sections were immunostained for cell cycle, epithelial and mesenchymal markers. Immunohistochemical analysis evidenced high Ki-67 positivity in stromal cells (mean of 20.9 cells/High power field). Epithelial cells displayed strong positivity for p53, p63 and cytokeratin 19. In addition to the case report, a systematic review of current knowledge is presented on the AFS's clinical-demographic features and prognostic factors. Based on the review, 88/99 cases were diagnosed as AFS, 9/99 as ameloblastic fibro-odontosarcoma and 2/99 as ameloblastic fibrodentinosarcoma. All these lesions displayed very similar clinical-demographic and prognostic features. Moreover, the review provided evidence that first treatment, regional metastasis, distant metastasis and local recurrence were significant prognostic values for malignant odontogenic mesenchymal lesions. Based on the findings, segregation among ameloblastic fibrosarcoma, ameloblastic fibrodentinosarcoma and ameloblastic fibro-odontosarcoma seems illogical, considering all these lesions have similar predilections and outcomes.
Topics: Adult; Female; Fibrosarcoma; Humans; Immunohistochemistry; Mandibular Neoplasms; Odontogenic Tumors
PubMed: 28492759
DOI: 10.1590/0103-6440201701050 -
Journal of Oral and Maxillofacial... 2021Solitary plasmacytoma of bone (SPB) is a localized form of plasma cell neoplasm where jaw involvement is rare. Distinguishing SPB from other plasma cell neoplasms is...
Solitary plasmacytoma of bone (SPB) is a localized form of plasma cell neoplasm where jaw involvement is rare. Distinguishing SPB from other plasma cell neoplasms is critical for treatment and survival. Here, a case of SPB of mandible in an elderly female is reported. Histopathological diagnosis of plasma cell neoplasm was confirmed immunohistochemically with MUM1 and CD138 positivity and multiple myeloma (MM) was ruled out on performing systemic workup. Prognosis of SPB worsens when it transforms into MM. A systematic review was undertaken with the objective to determine the factors affecting conversion of SPB to MM. An electronic search was undertaken with PubMed/MEDLINE, Web of Science and Science Direct. Fifty cases of SPB of jaw from 29 publications were reviewed. SPB commonly presents as a painless swelling. Radiographically, it is commonly seen as multilocular radiolucency with well-defined borders. Follow-up data showed that nine cases turned into MM in a mean duration of 1 year 9 months and 12 patients died after median disease-free survival of 6 years 9 months. Prognosis of SPB is found to be affected by tumor size (≥5 cm), anaplasia of tumor cells, Ki-67 labeling index, vascularity of the tumor, presence of clonal bone marrow plasma cells, serum immune globulin level, dose of radiotherapy and persistence of M protein after treatment. There is a need to identify prognostic subgroups in SPB based on these factors. Furthermore, studies are necessary for standardization of treatment protocol to halt or prolong the progression of SPB to MM.
PubMed: 34349446
DOI: 10.4103/jomfp.JOMFP_251_20 -
PloS One 2018In advanced prostate cancer, osteoclast inhibitors prevent and palliate skeletal related events associated with bone metastases. However, it is uncertain whether they... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In advanced prostate cancer, osteoclast inhibitors prevent and palliate skeletal related events associated with bone metastases. However, it is uncertain whether they play a disease-modifying role earlier in the course of the disease.
METHODS
Medline, EMBASE, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and ASCO conference proceedings were searched for randomized controlled trials that compared osteoclast inhibitors with placebo and/or standard of care (SOC) in patients with high-risk, non-metastatic prostate cancer. The primary outcome measure was incidence of new bone metastases; secondary outcomes included overall survival (OS), prostate cancer specific survival, mortality unrelated to prostate cancer, toxicity and health related quality of life outcomes. Results are presented as relative risk (RR) with 95% confidence intervals (CI).
RESULTS
Six randomized controlled trials (5947 participants) were included, five evaluating bisphosphonates and one denosumab. Overall, there was no difference in incidence of bone metastases between participants treated with osteoclast inhibitors versus placebo/SOC (RR 1.09, 95%CI 0.84-1.41, p = 0.51) however significant heterogeneity was observed between studies. The denosumab trial was the largest and only positive trial amongst the included studies (RR 0.83, 95%CI 0.73-0.95, p = 0.007). No significant difference was observed in OS (RR 0.99 95% CI 0.89-1.10, p = 0.84) nor prostate cancer specific survival (RR 1.12 95%CI 0.93-1.36, p = 0.24). Most studies reported increased rates of osteonecrosis of the jaw (5% or less) and hypocalcemia (2% or less) with osteoclast inhibitors.
CONCLUSIONS
While there is limited evidence that bisphosphonates alter the natural history of high-risk, non-metastatic prostate cancer, denosumab delays onset of bone metastases in this patient population. Neither class of osteoclast inhibitor demonstrated an impact on survival outcomes. Future trials with better defined patient selection and a robust definition for high risk disease is critical.
Topics: Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Diphosphonates; Humans; Male; Osteoclasts; Outcome Assessment, Health Care; Prostatic Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 29370211
DOI: 10.1371/journal.pone.0191455 -
PloS One 2015Ameloblastoma is the second most common odontogenic tumor, known to be slow-growing, persistent, and locally aggressive. Recent data suggests that ameloblastoma is best... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ameloblastoma is the second most common odontogenic tumor, known to be slow-growing, persistent, and locally aggressive. Recent data suggests that ameloblastoma is best treated with wide resection and adequate margins. Following primary excision, bony reconstruction is often necessary for a functional and aesthetically satisfactory outcome, making early diagnosis paramount. Despite earlier diagnosis potentially limiting the extent of resection and reconstruction, an understanding of the growth rate and natural history of ameloblastoma has been notably lacking from the literature.
METHOD
A systematic review of the literature was conducted by reviewing relevant articles from PubMed and Web of Science databases. Each article's level of evidence was formally appraised according to the Centre of Evidence Based Medicine (CEBM), with data from each utilized in a meta-analysis of growth rates for ameloblastoma.
RESULTS
Literature regarding the natural history of ameloblastoma is limited since the tumor is immediately acted upon at its initial detection, unless the patient voluntarily refuses a surgical intervention. From the limited data, it is derived that the highest estimated growth rate is associated with solid, multicystic type and the lowest rate with peripheral ameloblastomas. After meta-analysis, the calculated mean specific grow rate is 87.84% per year.
CONCLUSION
The growth rate of ameloblastoma has been demonstrated, offering prognostic and management information, particularly in cases where a delay in management is envisaged.
Topics: Adult; Aged; Ameloblastoma; Female; Humans; Jaw Neoplasms; Male; Middle Aged; Young Adult
PubMed: 25706407
DOI: 10.1371/journal.pone.0117241 -
European Review For Medical and... Dec 2019Medication-related osteonecrosis of the jaw (ONJ) is an adverse, severe and debilitating effect, which although infrequent, affects patients with osteoporosis or...
OBJECTIVE
Medication-related osteonecrosis of the jaw (ONJ) is an adverse, severe and debilitating effect, which although infrequent, affects patients with osteoporosis or neoplasm who take bisphosphonates, antiresorptive drugs, and/or antiangiogenic drugs. Its etiopathogenesis is unknown, although genetic causes have been postulated.
MATERIALS AND METHODS
This review analyzed articles published to date that have studied genetic factors associated with ONJ. Fifteen case-control studies were included, published between 2008 and 2018.
RESULTS
Five set out to determine genetic causes by means of genome-centered techniques, while ten do so by investigating gene-centered variants. Nine works found statistically significant associations between one or various single nucleotide polymorphisms (SNPs) and the appearance of ONJ. None of the studies coincided as to which genes present some association.
CONCLUSIONS
The review observed the moderate impact of genetic factors on the appearance of ONJ. It also showed the heterogeneity of the studies that have investigated ONJ to date. In future studies, involving international and interhospital collaboration will be necessary to recruit sample sizes of sufficient size, elaborate adequate study designs, obtain clear results, and advance our understanding of ONJ and make it possible to single out individual patients at risk.
Topics: Angiogenesis Inhibitors; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Diphosphonates; Humans
PubMed: 31841171
DOI: 10.26355/eurrev_201912_19652