Publications

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are currently used as supportive therapy for multiple myeloma (MM). However, the exact clinical role of bisphosphonates in MM remains unclear.

OBJECTIVES: This update of the first review published in 2002. We have also analyzed observational studies targeting osteonecrosis of jaw (ONJ).

SEARCH STRATEGY: We searched the literature using the methods outlined in the previous review. We also searched observational studies or case reports examining ONJ.

SELECTION CRITERIA: We selected RCTs with a parallel design related to the use of bisphosphonate in myeloma. We also selected observational studies or case reports examining bisphosphonates related to ONJ.

DATA COLLECTION AND ANALYSIS: We have reported pooled data using either hazard ratio or risk ratio and, when appropriate, as absolute risk reduction and the number needed to treat to prevent or to cause a pathological event. We have assessed statistical heterogeneity and reported I(2) statistic.

MAIN RESULTS: This review includes 17 trials with 1520 patients analyzed in bisphosphonates groups, and 1490 analyzed in control groups. In comparison with placebo/no treatment, the pooled analysis demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (RR= 0.74 (95% CI: 0.62 to 0.89), P = 0.001), total skeletal related events (SREs) (RR= 0.80 (95% CI: 0.72 to 0.89), P < 0.0001) and on amelioration of pain (RR = 0.75 (95% CI: 0.60 to 0.95), P = 0.01). We found no significant effect of bisphosphonates on overall survival (OS), progression-free survival (PFS), hypercalcemia or on the reduction of non-vertebral fractures. The indirect meta-analyses did not find the superiority of any particular type of bisphosphonate over others. Only two RCTs reported ONJ. The identified observational studies suggested that ONJ may be a common event (range: 0% to 51%).

AUTHORS' CONCLUSIONS: Adding bisphosphonates to the treatment of MM reduces pathological vertebral fractures, SREs and pain but not mortality. Assuming the baseline risk of 20% to 50% for vertebral fracture without treatment, we estimate that between eight and 20 MM patients should be treated to prevent vertebral fracture(s) in one patient. Assuming the baseline risk of 31% to 76% for pain amelioration without treatment, we estimate that between five to 13 MM patients should be treated to reduce pain in one patient. Also, with the baseline risk of 35% to 86% for SREs without treatment, we estimate that between six and 15 MM patients should be treated to prevent SRE(s) in one patient. No bisphoshphonate appears to be superior to others.

BACKGROUND: Decision curve analysis (DCA) has been proposed as an alternative method for evaluation of diagnostic tests, prediction models, and molecular markers. However, DCA is based on expected utility theory, which has been routinely violated by decision makers. Decision-making is governed by intuition (system 1), and analytical, deliberative process (system 2), thus, rational decision-making should reflect both formal principles of rationality and intuition about good decisions. We use the cognitive emotion of regret to serve as a link between systems 1 and 2 and to reformulate DCA.

METHODS: First, we analysed a classic decision tree describing three decision alternatives: treat, do not treat, and treat or no treat based on a predictive model. We then computed the expected regret for each of these alternatives as the difference between the utility of the action taken and the utility of the action that, in retrospect, should have been taken. For any pair of strategies, we measure the difference in net expected regret. Finally, we employ the concept of acceptable regret to identify the circumstances under which a potentially wrong strategy is tolerable to a decision-maker.

RESULTS: We developed a novel dual visual analog scale to describe the relationship between regret associated with "omissions" (e.g. failure to treat) vs. "commissions" (e.g. treating unnecessary) and decision maker's preferences as expressed in terms of threshold probability. We then proved that the Net Expected Regret Difference, first presented in this paper, is equivalent to net benefits as described in the original DCA. Based on the concept of acceptable regret we identified the circumstances under which a decision maker tolerates a potentially wrong decision and expressed it in terms of probability of disease.

CONCLUSIONS: We present a novel method for eliciting decision maker's preferences and an alternative derivation of DCA based on regret theory. Our approach may be intuitively more appealing to a decision-maker, particularly in those clinical situations when the best management option is the one associated with the least amount of regret (e.g. diagnosis and treatment of advanced cancer, etc).

WHENEVER A TRIAL IS CONDUCTED, THERE ARE THREE POSSIBLE EXPLANATIONS FOR THE RESULTS: a) findings are correct (truth), b) represents random variation (chance) or c) they are influenced by systematic error (bias). Random error is deviation from the 'truth' and happens due to play of chance (e.g. trials with small sample, etc.). Systematic distortion of the estimated intervention effect away from the 'truth' can also be caused by inadequacies in the design, conduct or analysis of a trial. Several studies have shown that bias can obscure up to 60% of the real effect of a healthcare intervention. A mounting body of empirical evidence shows that 'biased results from poorly designed and reported trials can mislead decision making in healthcare at all levels'. Poorly conducted and reported RCTs seriously compromise the integrity of the research process especially when biased results receive false credibility. Therefore, critical appraisal of the quality of clinical research is central to informed decision-making in healthcare. Critical appraisal is the process of carefully and systematically examining research evidence to judge its trustworthiness, its value and relevance in a particular context. It allows clinicians to use research evidence reliably and efficiently. Critical appraisal is intended to enhance the healthcare professional's skill to determine whether the research evidence is true (free of bias) and relevant to their patients.

BACKGROUND: Evidence bearing on the efficacy of tandem autologous hematopoietic transplant (AHCT) vs a single AHCT in patients with multiple myeloma (MM) is conflicting. We performed a systematic review and meta-analysis to synthesize the existing evidence related to the effectiveness of tandem vs single AHCT in patients with MM.

METHODS: We searched Medline, conference proceedings, and bibliographies of retrieved articles and contacted experts in the field to identify randomized controlled trials (RCTs) reported in any language that compared tandem with single AHCT in patients with MM through March 31, 2008. Endpoints were overall survival (OS), event-free survival (EFS), response rate, and treatment-related mortality (TRM). Data were pooled under a random-effects model.

RESULTS: Six RCTs enrolling 1803 patients met the inclusion criteria. Patients treated with tandem AHCT did not have better OS (hazard ratio [HR] for mortality for patients treated with tandem transplant vs single transplant = 0.94; 95% confidence interval [CI] = 0.77 to 1.14) or EFS (HR = 0.86; 95% CI = 0.70 to 1.05). Response rate was statistically significantly better with tandem AHCT (risk ratio = 0.79, 95% CI = 0.67 to 0.93), but with a statistically significant increase in TRM (risk ratio = 1.71, 95% CI = 1.05 to 2.79). There was statistically significant heterogeneity among RCTs for OS and EFS.

CONCLUSION: In previously untreated MM patients, use of tandem AHCT did not result in improved OS or EFS. We conclude that tandem AHCT is associated with improved response rates but at risk of clinically significant increase in TRM.

Increased insight into the role of B lymphocytes in the pathophysiology of graft-versus-host disease has led to a number of studies assessing the efficacy of the anti-CD20 monoclonal antibody (mAb) rituximab in treating steroid-refractory chronic graft-versus-host disease (cGVHD). Findings vary greatly among these studies, however. We conducted a systematic review to summarize the totality of evidence on the efficacy of rituximab in steroid-refractory cGVHD. We performed a PubMed search and contacted experts in the field to identify relevant studies. Endpoints included overall response rate (including organ-specific) and ability of rituximab to allow dosage reduction of immunosuppressive therapies. Data were pooled under a random-effects model. Seven studies (3 prospective and 4 retrospective, with a total of 111 patients) met the inclusion criteria. The pooled proportion of overall response was 0.66 (95% confidence interval=0.57 to 0.74). There was no heterogeneity among the pooled studies. Response rates were 13% to 100% for cGVHD of the skin, 0 to 83% for cGVHD of the oral mucosa, 0 to 66% for cGVHD of the liver, and 0 to 38% for cGVHD of the lung. Common adverse events were related to infusion reactions or infectious complications. The relatively small number of patients and the varying criteria for reporting organ response and dosage reduction of steroids, among other limitations, hinders our ability to reach definitive conclusions on the overall efficacy of rituximab for cGVHD involving other organs.

Significant uncertainty exists regarding the efficacy of high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) for the treatment of patients with primary systemic (AL) amyloidosis. We performed a systematic review and meta-analysis to evaluate the efficacy of AHCT versus conventional chemotherapy (CC) in patients with AL amyloidosis using methodology recommended by the Cochrane Collaboration. A comprehensive literature search yielded 820 studies. Twelve studies met the inclusion criteria: 1 randomized controlled trial (RCT), 2 other controlled studies, and 9 single-arm trials. The 1 RCT and 2 controlled studies compared AHCT and CC, and 9 single-arm studies assessed the efficacy of AHCT without a control. The pooled hazard ratio for overall survival (OS) in the 3 controlled studies was 1.79 (95% confidence interval [CI] = 1.11 to 2.91) favoring CC. The pooled proportion for mortality in the single-arm studies (n = 7) was 0.35 (95% CI = 0.25 to 0.46). The pooled odds ratio for complete hematologic response (CHR) from 2 controlled studies was 0.64 (95% CI = 0.25 to 1.64), indicating no difference between AHCT and CC. In the single-arm studies, the pooled proportion for CHR was 0.35 (95% CI = 0.26 to 0.44), and the pooled proportion for treatment-related mortality (TRM) was 0.12 (95% CI = 0.09 to 0.14). In the controlled studies, there was no heterogeneity for any outcome; however, in the single-arm studies, there was a significant heterogeneity for the outcomes of OS, CHR, renal response, and partial hematologic response. Our findings indicate that AHCT does not appear to be superior to CC in improving OS in patients with AL amyloidosis. But the quality of our evidence is low, indicating a need for well-designed and adequately powered RCTs to better address the role of AHCT in AL amyloidosis.

BACKGROUND: The evaluation of research output, such as estimation of the proportion of treatment successes, is of ethical, scientific, and public importance but has rarely been evaluated systematically. We assessed how often experimental cancer treatments that undergo testing in randomized clinical trials (RCTs) result in discovery of successful new interventions.

METHODS: We extracted data from all completed (published and unpublished) phase 3 RCTs conducted by the National Cancer Institute cooperative groups since their inception in 1955. Therapeutic successes were determined by (1) assessing the proportion of statistically significant trials favoring new or standard treatments, (2) determining the proportion of the trials in which new treatments were considered superior to standard treatments according to the original researchers, and (3) quantitatively synthesizing data for main clinical outcomes (overall and event-free survival).

RESULTS: Data from 624 trials (781 randomized comparisons) involving 216 451 patients were analyzed. In all, 30% of trials had statistically significant results, of which new interventions were superior to established treatments in 80% of trials. The original researchers judged that the risk-benefit profile favored new treatments in 41% of comparisons (316 of 766). Hazard ratios for overall and event-free survival, available for 614 comparisons, were 0.95 (99% confidence interval [CI], 0.93-0.98) and 0.90 (99% CI, 0.87- 0.93), respectively, slightly favoring new treatments. Breakthrough interventions were discovered in 15% of trials.

CONCLUSIONS: Approximately 25% to 50% of new cancer treatments that reach the stage of assessment in RCTs will prove successful. The pattern of successes has become more stable over time. The results are consistent with the hypothesis that the ethical principle of equipoise defines limits of discoverability in clinical research and ultimately drives therapeutic advances in clinical medicine.

PURPOSE: A meta-analytic approach was used to estimate the frequency of: (a) microsatellite instability-high (MSI-H) phenotype in unselected ovarian cancers and (b) various histologic subtypes of mismatch repair (MMR)-deficient epithelial ovarian cancers.

METHODS: A systematic search of the Medline electronic database was conducted to identify articles published between January 1, 1966, and December 31, 2007, that examined MMR deficiency in ovarian cancers. Data were extracted on the study population, sample size, MSI-H frequency, and histology of MMR-deficient ovarian tumors.

RESULTS: The pooled proportion of MSI-H ovarian cancers was 0.12 [95% confidence interval (CI), 0.08-0.17] from 18 studies with 977 cases. The proportion of histologic subtypes in the pooled analysis from 15 studies with 159 cases was serous at 0.32 (95% CI, 0.20-0.44), mucinous at 0.19 (95% CI, 0.12-0.27), endometrioid at 0.29 (95% CI, 0.22-0.36), clear cell at 0.18 (95% CI, 0.09-0.28), and mixed at 0.24 (95% CI, 0.07-0.47). There was significant heterogeneity between studies.

CONCLUSIONS: The frequency of the MSI-H phenotype in unselected ovarian cancers approximates 12%. MMR-deficient ovarian cancers also seem to be characterized by an overrepresentation of nonserous histologic subtypes. Knowledge of histologic subtype may aid clinicians in identifying the relatively large proportion of ovarian cancers due to MMR defects; such knowledge has potential implications for medical management.