Skeletal-related Events In Cancer Patients Research Articles

P40.08 Bone-Targeted Agents Improve Survival in High Bone Tumor Burden Advanced Non-Small-Cell-Lung Cancer Patients Treated With PD-(L)1 Inhibitors

Bone-targeted agents (BTA) prevent skeletal-related events in cancer patients (pts) treated with chemotherapy (CT) with no significant impact on overall survival (OS). Among BTA, denosumab (DN) improved OS compared to zoledronic acid (ZA) in a subgroup analysis of advanced non-small-cell lung cancer (aNSCLC) pts with bone metastases (BM), while in the SPLENDOUR trial the addition of DN to 1st-line CT in aNSCLC did not improve survival. Currently, the impact of BTA in immune-checkpoint inhibitors (ICIs) treated aNSCLC with BM is unclear.

Acute-phase reaction induced by zoledronate and its effect on prognosis of patients with advanced non-small cell lung cancer

ObjectivesZoledronate (ZOL) is usually used for prevention of skeletal-related events in cancer patients with bone metastases. The first administration of ZOL is occasionally associated with development of acute-phase reaction (APR), which is due to activation of γδ T cells. ZOL-related APR was associated with better overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in our previous retrospective study. However, it remains to be clarified whether γδ T cells are more activated in patients who experienced ZOL-related APR, and whether γδ T cell activation is involved in prolongation of OS. Materials and MethodsTwenty-three patients with advanced NSCLC were recruited between 2012 and 2014 in this study. We administered ZOL to participants with standard care. The patient characteristics, change in γδ T cell counts and cytokines, OS, and skeletal-related event-free survival were compared between patients with APR (APR group) and those without APR (non-APR group). ResultsTen patients (43.5%) experienced a ZOL-related APR. The number of γδ T cells at baseline in the APR group was significantly higher than that in the non-APR group. Serum interleukin-6 and tumor necrosis factor-α in the APR group were significantly increased, but no change in the number of γδ T cells was observed after the first administration of ZOL in both groups. OS in the APR group was significantly longer than that in the non-APR group (median survival time: 23.1 vs. 14.5 months, p < 0.01). ConclusionWe showed that APR is related to higher numbers of γδ T cells at baseline and increased cytokines after the first ZOL administration, but not to proliferative responses of γδ T cells. In addition, better OS was observed in the APR group. Therefore, the number of γδ T cells might be a prognostic marker in patients with NSCLC.

Exploiting machine learning for predicting skeletal-related events in cancer patients with bone metastases.

The aim of the bone metastases (BM) treatment is to prevent the occurrence of skeletal-related events (SREs). In clinical, physicians could only predict the occurrence of SREs by subjective experience. Machine learning (ML) could be used as predictive models in the medical field. But there is no published research using ML to predict SREs in cancer patients with BM. The purpose of this study was to assess the associations of clinical variables with the occurrence of SREs and to subsequently develop prediction models to help identify SREs risk groups.We analyzed 1143 cancer patients with BM. We used the statistical package of SPSS and SPSS Modeler for data analysis and the development of the prediction model. We compared the performance of logistic regression (LR), decision tree (DT) and support vector machine(SVM). The results suggested that Visual Analog Scale (VAS) scale was a key factor to SREs in LR, DT and SVM model. Modifiable factors such as Frankel classification, Mirels score, Ca, aminoterminal propeptide of type I collagen (PINP) and bone-specific alkaline phosphatase (BALP) were identified. We found that the result of applying LR, DT and SVM classification accuracy was 79.2%, 85.8% and 88.2%, with 9, 4 and 8 variables, respectively.In conclusion, DT and SVM achieved higher accuracies with smaller number of variables than the number of variables used in LR. ML techniques can be used to build model to predict SREs in cancer patients with BM.

Interpreting results from oncology clinical trials: a comparison of denosumab to zoledronic acid for the prevention of skeletal-related events in cancer patients

BackgroundCritically reviewing the design, endpoints, and results of clinical trials can be challenging to health care professionals. This paper will review the basic methods of presenting clinical outcomes in randomized trials and will focus on the number needed to treat (NNT) concept. NNT will then be applied to the case of bone-targeted therapies denosumab and zoledronic acid, which are used for the prevention of skeletal-related events (SREs) in a variety of disease sites.MethodsA Medline search was performed to identify randomized trials comparing denosumab to zoledronic acid for the prevention of SREs in patients with advanced breast, prostate, and other cancer sites. The data were extracted, and point estimates for the primary and secondary trial endpoints were converted into the NNT parameter.ResultsNNT represents the number of patients that need to be treated with a new intervention in order to avoid one additional patient developing the event and is a powerful approach that can be used to make sense of numerical results from clinical trials. In patients with advanced breast, prostate, and other cancer sites, 18, 22, and 21 patients, respectively, would need to be treated with denosumab for at least 24 months to avoid one patient developing an SRE.ConclusionsThe NNT approach is a simple and effective method to express the findings of randomized trials in a clinically meaningful way. In this analysis, the incremental benefits of denosumab would be realized when a minimum of 18 to 22 patients are treated for a prolonged duration. Clinicians would have to weigh the costs and benefits between denosumab and zoledronic acid when bone-targeted therapy is indicated.

Update on the Pharmacological Prevention of Skeletal-related Events in Cancer Patients

Metastases to the bone are a frequent complication of advanced cancer. Bone metastases have been linked to skeletal-related events, which is the composite endpoint used in clinical trials evaluating therapy to minimize these complications. This article discusses bisphosphonates, which are the historical standard for the prevention of skeletal-related events in patients with metastases from solid tumors and multiple myeloma, and denosumab, which is the first Food and Drug Administration-approved receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitor.

Serum C-telopeptide levels predict the incidence of skeletal-related events in cancer patients with secondary bone metastases

We evaluated serum C-telopeptides (CTX) to see whether they may be useful as predictive markers for disease progression in cancer patients with bone metastases who are being treated with zoledronic acid (ZA). This was a prospective, nonrandomised study in which 26 patients with solid tumours and confirmed bone metastases were treated with ZA (4 mg every 3-4 weeks) for 24 months or until a skeletal-related event (SRE) was observed. Serum CTX levels were determined at baseline and 6, 12, 18 and 24 months after study initiation. SRE were evaluated using bone scintigraphy. Study participants had prostate (50%), breast (31%), lung (11%) or bladder (8%) tumours. Mean age was 69 (range 52-84) years, and 65% men. At baseline, overall mean CTX levels were 562.47 ± 305.17 pg/dl. Patients who showed disease progression during the study period showed significantly higher CTX levels at baseline and after 18 months of ZA treatment than patients who did not progress (p = 0.040 and p = 0.006, respectively). Patients with ≥ 5 bone metastases at diagnosis had significantly higher CTX levels after 18 months of ZA treatment than patients with < 5 bone metastasis (p = 0.001). Similarly, at 12 and 18 months, patients without SRE had significantly lower CTX levels than patients in whom a SRE was observed (p = 0.005 and p = 0.001, respectively). Changes in serum CTX levels seem to predict the potential for tumour control and the likelihood of developing an SRE in a sample of patients with solid tumours and bone metastases treated with ZA.

Pharmacologic Prevention of Skeletal-Related Events in Cancer Patients

Intravenous bisphosphonates are a standard therapeutic option in the prevention of skeletal-related events in metastatic breast and prostate cancer as well as multiple myeloma with bone involvement. Denosumab represents a new class of medications that inhibits the RANK ligand and is currently being evaluated to prevent skeletal-related events.

Preventing metastases to bone: Denosumab or bisphosphonates?

Preventing metastases to bone: Denosumab or bisphosphonates?

345 POSTER Nomograms to predict outcome after preoperative chemotherapy for breast cancer

Background: Complications from skeletal-related events (SREs) constitute a challenge in the care of patients with metastatic bone disease (MBD) that originated from any type of malignancy.Objective: The purpose of this article was to compare the efficacy of clodronate, pamidronate, and zoledronate with that of placebo in reducing morbidity and overall mortality in cancer patients with MBD.Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched (from inception to January 2009) to retrieve randomized clinical trials that evaluated the bisphosphonates of interest. The search included articles published in English, French, Italian, Portugese, and Spanish. Patients with a definite (ie, biopsy-proven) diagnosis of MBD were included in the analysis. We extracted and combined data from studies that reported the number of patients with SREs and mortality data. A random-effects, meta-analytic model was applied in all calculations. The Jadad scale was used to assess the quality of study reporting.Results: The literature search identified 62 potential full-text studies; 44 of these studies were excluded and 18 were evaluated. The mean (SD) quality of reporting of the included studies was 57.8% (22.6%), or 2.89/5 (1.1/5). Each of the 3 drugs was found to be more effective than placebo in preventing all SREs in cancer patients with MBD. The relative risk of developing SREs was 0.70 (95% CI, 0.61–0.81; N = 1211) for zoledronate, 0.81 (95% CI, 0.73–0.91; N = 2251) for pamidronate, and 0.87 (95% CI, 0.75–1.00; N = 681) for clodronate. However, no clear advantage of one drug over the others was observed (CIs overlapped substantially). None of the bisphosphonates was more beneficial than placebo in reducing the number of deaths in the course of the trials (P = NS).Conclusion: Clodronate, pamidronate, and zoled-ronate were associated with reductions in morbidity in cancer patients with MBD with regard to preventing SREs, but were not associated with a reduction in overall mortality.