To characterize the clinical features, associated disorders, and treatment of necrobiotic xanthogranuloma (NXG), a rare non-Langerhans cell histiocytosis, we conducted a retrospective review of pathologically confirmed NXG at Mayo Clinic Arizona from 1987 to June 2017. Data on clinical findings, laboratory findings, associated disorders, therapy, and response to therapy were extracted. Nineteen patients were identified. Mean age was 54 years (range, 17-84) with equal gender distribution. Median follow-up was 5.5 years (range, 1-18). Most patients had a detectable monoclonal protein (84%), and IgG kappa constituted 58%. The most common cutaneous lesions involved the periorbital region (53%). The majority of patients had extracutaneous manifestations, most commonly affecting the liver (32%) and the sinuses (21%). Hematologic malignancies were diagnosed in 26% of patients and included Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), smoldering myeloma, and multiple myeloma. The most common treatment was chlorambucil with or without systemic corticosteroids. Response was seen in most patients (95%), and most patients received 1-3 lines of therapy (74%). NXG is a reactive histiocytic disorder that commonly involves multiple organ systems and requires a high degree of clinical suspicion for accurate diagnosis. Treatment decisions should be based on coexisting conditions and pattern of disease involvement.

IMPORTANCE To date, an empirical evaluation of the quality of control arms in randomized clinical trials (RCTs) leading to anticancer drug approvals by the US Food and Drug Administration (FDA) has not been undertaken. OBJECTIVE We sought to estimate the percentage of RCTs that used a control arm deemed suboptimal and led to FDA approval of anticancer drugs from January 1, 2013, to July 31, 2018. DESIGN, SETTING, AND PARTICIPANTS This quality improvement study included 143 anticancer drug approvals granted by the FDA from January 1, 2013, to July 31, 2018. All approvals based on single-arm studies (48 approvals) were excluded. Approvals based on RCTs were further investigated and each trial was analyzed for design, time of patient accrual, control arm, and primary end point. Standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of trial enrollment. The percentage of approvals based on RCTs that used suboptimal control arms was then calculated. The quality of the control arm was deemed suboptimal if the choice of control agent was restricted to exclude a recommended agent, the control arm was specified but the recommended agent was unspecified, and if prior RCT data had demonstrated that the control agent was inferior to an available alternative. MAIN OUTCOMES AND MEASURES Estimated percentage of RCTs that used suboptimal control arms that led to FDA approval of anticancer agents between January 1, 2013, to July 31, 2018. RESULTS A total of 145 studies that led to 143 drug approvals between January 1, 2013, and July 31, 2018, were included. Of these studies, 48 single-arm studies were excluded. The remaining 97 studies led to 95 drug approvals. Of these 95 approvals, 16 (17%) were based on RCTs with suboptimal control arms; 15 were international trials, and 1 was conducted in the United States. The type of approval was regular in 15 trials and accelerated in 1 trial. When categorized by the nature of suboptimal control, 4 (25%) trials omitted active treatment in control arm by limiting investigator's choice, 11 (63%) trials omitted active treatment in the control arm by using a control agent known to be inferior to other available agents or not allowing combinations, and 1 (13%) trial used a previously used treatment in the control arm with a known lack of benefit associated with reexposure. CONCLUSIONS AND RELEVANCE Although anticancer drug approvals are increasing, a proportion of these drugs are reaching the market without proven superiority to what is considered the standard of care at the time of patient enrollment in pivotal trials. The choice of control arm should be optimized to ensure that new anticancer agents being marketed are truly superior to what most clinicians would prescribe outside a clinical trial setting.

CESM was comparable to MRI in assessing residual malignancy after completion of NST.