The use of and adherence to CTCAE v3.0 in cancer clinical trial publications The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT) De-escalated administration of bone-targeted agents in patients with breast and prostate cancer—A survey of Canadian oncologists Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial A multicenter and open label clinical trial of zoledronic acid 4 mg in patients with hypercalcemia of malignancy.
Background The Common Terminology Criteria for Adverse Events , Version 3.0 ( CTCAE v3.0 ) was released in 2003 , and has been widely used as the predominant set of toxicity criteria for cancer clinical trials and scientific meetings . However , the degree to which the elements of CTCAE v3.0 are followed in oncology publications has not been comprehensively evaluated . Methods We review ed phase III r and omized clinical trials evaluating systemic cancer therapies , published between Jan 1 , 2012 and December 31 , 2013 , to identify eligible studies that explicitly mentioned using CTCAE v3.0 as the toxicity criteria . A 10-point score based on adherence to CTCAE v3.0  was used to assess the studies . Multivariate linear regression was used to identify features associated with improved adherence . Results In total , 104 publications reporting data on 86,957 patients were included in this analysis .  The mean total score for adherence to all four elements of CTCAE v3.0 was 4.03 on a 10-point scale ( range , 1 to 9 ) , with 16 publications ( 15 % ) having total scores ≤2 . Highly heterogeneous and unst and ardized adverse event terms were frequently used . In addition , Supra-ordinate terms , terms using ‘ Other , specify ’ , and Grade s were often used incorrectly . The multivariate regression model revealed that the absence of a placebo ( P=0.003 ) and a higher total number of AE terms in the table ( P<0.001 ) were independent predictors of a lower total score . Conclusion Given the importance of underst and ing the toxicity of new treatments , better adherence to CTCAE v3.0 should be encouraged to ensure the consistency and comparability of toxicity data across different studies Zoledronic acid 5 mg ( ZOL ) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis . To investigate long-term effects of ZOL on bone mineral density ( BMD ) and fracture risk , the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly – Pivotal Fracture Trial ( HORIZON-PFT ) was extended to 6 years . In this international , multicenter , double-blind , placebo-controlled extension trial , 1233 postmenopausal women who received ZOL for 3 years in the core study were r and omized to 3 additional years of ZOL ( Z6 , n = 616 ) or placebo ( Z3P3 , n = 617 ) . The primary endpoint was femoral neck ( FN ) BMD percentage change from year 3 to 6 in the intent-to-treat ( ITT ) population . Secondary endpoints included other BMD sites , fractures , biochemical bone turnover markers , and safety . In years 3 to 6 , FN-BMD remained constant in Z6 and dropped slightly in Z3P3 ( between-treatment difference = 1.04 % ; 95 % confidence interval 0.4 to 1.7 ; p = 0.0009 ) but remained above pretreatment levels . Other BMD sites showed similar differences . Biochemical markers remained constant in Z6 but rose slightly in Z3P3 , remaining well below pretreatment levels in both . New morphometric vertebral fractures were lower in the Z6 ( n = 14 ) versus Z3P3 ( n = 30 ) group ( odds ratio = 0.51 ; p = 0.035 ) , whereas other fractures were not different . Significantly more Z6 patients had a transient increase in serum creatinine > 0.5 mg/dL ( 0.65 % versus 2.94 % in Z3P3 ) . Nonsignificant increases in Z6 of atrial fibrillation serious adverse events ( 2.0 % versus 1.1 % in Z3P3 ; p = 0.26 ) and stroke ( 3.1 % versus 1.5 % in Z3P3 ; p = 0.06 ) were seen . Postdose symptoms were similar in both groups . Reports of hypertension were significantly lower in Z6 versus Z3P3 ( 7.8 % versus 15.1 % , p < 0.001 ) . Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects , and therefore , after 3 years of annual ZOL , many patients may discontinue therapy up to 3 years . However , vertebral fracture reductions suggest that those at high fracture risk , particularly vertebral fracture , may benefit by continued treatment . ( Clinical Trials.gov identifier : NCT00145327 ) . © 2012 American Society for Bone and Mineral Research Objective Questions remain regarding the optimal use of bone-targeted agents in patients with metastatic bone disease . The purpose of this study was to assess current clinical practice regarding the use and administration of bone-targeted agents by Canadian oncologists in patients with metastatic breast and prostate cancer . Methods A survey was design ed to explore ; bone-targeted agent use in metastatic bone disease , variability in the choice and the frequency of administration of these agents . Opinions were sought on potential outcomes for future trials . Results A total of 193 clinicians were contacted and 90 completed our survey ( response rate 49 % after adjustment for inactivity ) . Survey respondents were medical oncologists ( 71.1 % ) , radiation oncologists ( 21.1 % ) and urologists ( 7.8 % ) . The findings suggest that once bone-targeted agents are started they are rarely discontinued . More agents are used in breast cancer than in prostate cancer . There was considerable interest in performing studies of de-escalated therapy in both breast and prostate cancer . Physicians requested ( 86 % ) that the primary study endpoint be the occurrence of skeletal related events and not biomarker driven . Conclusions Despite clinical practice guidelines and widespread use , significant areas of clinical equipoise with respect to use of bone-targeted agents exist . Findings from this survey suggest that physicians are interested in de-escalated therapy for both breast and prostate patients . However , the use of multiple agents in breast cancer and the desire for skeletal related events to be the primary endpoint means that very large r and omized studies will be required This study analyzed the anti-myeloma effect of zoledronic acid monotherapy by investigating patients at the time of asymptomatic biochemical relapse . One hundred patients were r and omized to receive either zoledronic acid ( 4 mg iv/4 weeks , 12 doses ) ( n=51 ) or not ( n=49 ) . Experimental and control groups were well balanced for disease and prognostic features . Zoledronic acid did not show an antitumor effect according to changes in M-component . However , there were fewer symptomatic progressions in the experimental group than in the control group ( 34 versus 41 , respectively ; P=0.05 ) result ing in a median time to symptoms of 16 versus 10 months ( P=0.161 ) . The median time to next therapy was also slightly longer for the treated group than the untreated , control group ( 13.4 versus 10.1 months ) , although the difference was not statistically significant ( P=0.360 ) . The pattern of relapses was different for treated versus control patients : progressive bone disease ( 8 versus 20 ) , anemia ( 24 versus 18 ) , renal dysfunction ( 1 versus 2 ) , and plasmacytomas ( 1 versus 1 , respectively ) . This concurred with fewer skeletal-related events in the treated group than in the control group ( 2 versus 14 ) , with a projected 4-year event proportion of 6 % versus 40 % ( P<0.001 ) . In summary , zoledronic acid monotherapy does not show an antitumor effect on biochemical relapses in multiple myeloma , but does reduce the risk of progression with symptomatic bone disease and skeletal complications . This trial was registered in the Clinical Trials.gov data base with code BACKGROUND Hypercalcemia of malignancy is a serious complication of cancer . The objective of this study was to investigate the efficacy and safety of zoledronic acid , a new-generation bisphosphonate and the most potent inhibitor of bone resorption identified to date , for hypercalcemia of malignancy in Japanese patients . METHODS Patients with hypercalcemia of malignancy , defined as an albumin-corrected serum calcium level > or = 12.0 mg/dl , were treated with a single dose of zoledronic acid , 4 mg , by 15 min infusion . Clinical end-points included the proportion of patients with complete response , which was defined as a decrease of corrected serum calcium < or = 10.8 mg/dl by day 10 , and time to relapse , which is defined as the duration in days between the date of infusion and last available corrected serum calcium < 11.6 mg/dl . RESULTS Twenty-seven patients were enrolled in this study and 25 patients were evaluable for the efficacy of zoledronic acid . The mean corrected serum calcium level decreased from 14.5 to 9.6 mg/dl by day 10 . The complete response rate was 84 % . The median time to relapse was 23 days , ranging from 0 to 56 days . The most frequently observed adverse event was fever ( < or = 38 degrees C ) . Electrolyte abnormalities suspected to be drug related including grade 3 or 4 hypocalcemia , hypophosphatemia and hypokalemia were observed in 11 patients ; however , all patients were asymptomatic . No serious adverse events associated with renal toxicity were reported . CONCLUSIONS Zoledronic acid is well tolerated and is effective for hypercalcemia of malignancy in Japanese patients
Zoledronic acid is used to treat patients with bone metastasis , but the optimal dosing interval remains controversial .
We therefore performed a systematic review and meta- analysis to compare the efficacy and safety of a 12-week interval of zoledronic acid with the st and ard 4-week interval .