Efficacy and toxicity of extending bone modifying agents beyond two years for bone metastases in breast or castrate-resistant prostate cancer patients: A systematic review.
Bibliographic record
Abstract
e24083 Background: Randomized clinical trials evaluated bone modifying agents (BMAs) such as bisphosphonates and denosumab for bone metastases for 1-2 years in duration even though BMA therapy is commonly administered for much longer. A systematic review on the risk-benefit of continuing BMAs for longer than 2 years in breast cancer or castrate-resistant prostate cancer was conducted. Methods: Medline, Embase and Cochrane Register of Controlled Trials were searched (1970 - February 2019) for randomized studies, observational studies, and case series reporting on BMA efficacy and toxicity beyond 2 years. Efficacy was assessed by skeletal-related event (SRE) rates and quality of life metrics. Toxicity was assessed by rates of osteonecrosis of the jaw (ONJ), renal impairment, hypocalcemia, and atypical femoral fractures (AFF). Results: Of 2107 citations, 64 studies were identified. A total of 3 prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Three studies [zoledronate (ZOL) (n = 481), pamidronate (PAM) (n = 87), PAM-ZOL (n = 43) ibandronate (n = 30)] reported on SRE-related endpoints. Only one study reported SRE rates based on duration of BMA exposure and showed reduced SRE rates from 27.6% (0-24 months) to 15.5% ( > 24 months) over time. None reported on quality of life. All 12 studies [denosumab (n = 948), ZOL (n = 1036), PAM (n = 163), PAM-ZOL (n = 522), ibandronate (n = 118)] reported on at least one toxicity outcome. Data from 7 bisphosphonate studies (n = 1077) and 1 denosumab study (n = 948) reported on ONJ incidence. In 3 studies (n = 67, n = 221, n = 948), ONJ incidence ranged from 1-4% in the first 2 years and from 3.8-18% beyond 2 years. In another study (n = 252), the cumulative hazard of ONJ was 0% (1% ZOL), 3% (7% ZOL), 7% (21% ZOL) and 11% (21% ZOL) at 12, 24, 36, and 48 months, respectively (p = 0.005); 4 remaining studies reported 1 (n = 181), 3 (n = 57), 7 (n = 99) and 2 (n = 200) cases of ONJ, all after 24 months. Incidence of clinically significant hypocalcemia ranged from 1-2%. Incidence of severe renal function decline was ≤ 3%. AFF occurred in two subjects in one of two studies after 37 and 79 months of BMA exposure. Conclusions: Although the evidence informing the use of BMA is heterogeneous and based on retrospective analysis, BMA exposure beyond 2 years is associated with reduced SRE risk and increased ONJ incidence. Prospective randomized studies addressing the use of BMA for more than 2 years is needed with greater emphasis on quality of life.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.013 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.008 | 0.007 |
| Bibliometrics | 0.005 | 0.007 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".