Oren Levine

The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index

OBJECTIVES A P-value <0.05 is one metric used to evaluate the results of a randomized controlled trial (RCT). We wondered how often statistically significant results in RCTs may be lost with small changes in the numbers of outcomes. STUDY DESIGN AND SETTING A review of RCTs in high-impact medical journals that reported a statistically significant result for at least one dichotomous or time-to-event outcome in the abstract. In the group with the smallest number of events, we changed the status of patients without an event to an event until the P-value exceeded 0.05. We labeled this number the Fragility Index; smaller numbers indicated a more fragile result. RESULTS The 399 eligible trials had a median sample size of 682 patients (range: 15-112,604) and a median of 112 events (range: 8-5,142); 53% reported a P-value <0.01. The median Fragility Index was 8 (range: 0-109); 25% had a Fragility Index of 3 or less. In 53% of trials, the Fragility Index was less than the number of patients lost to follow-up. CONCLUSION The statistically significant results of many RCTs hinge on small numbers of events. The Fragility Index complements the P-value and helps identify less robust results.

Systemic Therapy for Previously Untreated Advanced BRAF-Mutated Melanoma: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials

Importance Multiple effective first-line systemic treatment options are available for patients with advanced BRAF-mutated melanoma. A lack of head-to-head randomized clinical trials (RCTs) comparing targeted and immunotherapies leaves uncertainty regarding optimal first-line treatment. Objective To estimate the relative efficacy and safety of systemic therapies for advanced, treatment-naive, BRAF-mutated melanoma. Data Sources We searched MEDLINE, Embase, and the Cochrane Central Registry of Controlled Trials for phase 2 or 3 RCTs published up until April 29, 2016. Study Selection We included RCTs in which at least 1 intervention was a targeted (BRAF or MEK) or an immune checkpoint (cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor. Data Extraction and Synthesis Two reviewers performed study selection, data abstraction, and risk of bias assessment. We performed a Bayesian network meta-analysis using a fixed-effect model to combine direct comparisons with indirect evidence. We estimated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (OR) for objective response rate (ORR) and serious adverse events. Results Sixteen eligible articles reporting 15 RCTs involving 6662 patients assigned to 1 of 10 treatment strategies were included. Both BRAF/MEK and PD-1 were associated with improved OS benefit compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor. There was no significant difference in OS between BRAF/MEK and PD-1 (HR, 1.02; 95% credible interval [CrI], 0.72-1.45). The network meta-analysis showed a significant advantage of BRAF/MEK compared with all other treatment strategies for PFS. BRAF/MEK was associated with higher ORR (OR, 2.00; 95% CrI, 1.64-2.45) compared with BRAF alone, with both being superior in achieving ORR compared with other treatments. Chemotherapy and PD-1 were associated with lowest risk of serious adverse events. There was no significant difference in the risk of serious adverse events between chemotherapy and PD-1 (OR, 1.00; 95% CrI, 0.74-1.34). Conclusions and Relevance Compared with other treatments, BRAF/MEK and PD-1 inhibition significantly improved OS. The favorable safety profile of PD-1 inhibitors supports using this option as first-line therapy in circumstances where rapid response is not a priority.

Systemic therapy for previously untreated advanced BRAF-mutated melanoma: navigating a shifting landscape

Treatment of advanced cutaneous melanoma has rapidly evolved over recent years. This aggressive form of skin cancer, when not amenable to surgical resection due to locoregional or distant spread of tumor, has been associated with very poor prognosis [1]. Until recently, advanced melanoma was considered a fatal diagnosis with very few exceptions. Historically, high-dose IL-2 was offered to highly selected patients with limited comorbidity and excellent functional status for a small chance of durable disease control; however, this therapy is associated with severe, sometimes, life-threatening toxicity [2]. Cytotoxic chemotherapy was the standard of care for decades despite a lack of evidence i ndicating survival benefit [3]. Two major advances in this field have revolutionized the treatment landscape. With the development of molecularly targeted agents and immunotherapies, chemotherapy has largely been replaced as a first-line systemic treatment. Mutation in the BRAF (V600) gene has been identified as a highly prevalent oncogene leading to constitutive activation of the RAF/MEK/ERK cell signaling pathway [4]. Present in 40–60% of cutaneous melanoma cases [4,5], the protein product of this oncogene can be selectively targeted to arrest malignant cell growth. Targeted therapeutic agents including the tyrosine kinase inhibitors vemurafenib and dabrafenib have shown significant antineoplastic activity and clinical benefit for patients with advanced, BRAF-mutated melanoma [6,7]. Clinical responses with these small-molecule agents, however, are of limited duration, in part due to reactivation of the MAPK pathway leading to drug resistance [8]. Additionally, secondary skin malignancies can develop due to paradoxical activation of this pathway in cells with nonmutated BRAF [9]. Specific inhibitors of the MEK protein (which lies downstream of BRAF) including trametinib and cobimetinib have been developed, and the former has shown some clinical benefit as monotherapy [10]. The combination of BRAF and MEK inhibition, as compared with single-agent inhibition, has shown prolonged responses by delaying drug resistance and decreased incidence of skin-related adverse events [8,11]. Thus, the repertoire of targeted therapies has expanded. The second breakthrough was the discovery of immune-checkpoints or co-regulatory molecules responsible for dampening immune response. Mechanisms to suppress T-cell activation are important to avoid autoimmunity after an infectious insult, yet these protective mechanisms can be exploited by tumor cells to avoid immune attack. In fact, immune evasion is now recognized as one of the hallmarks of cancer. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed celldeath protein 1 (PD-1) have been characterized as important immune-checkpoints [12,13]. Systemic therapy for previously untreated advanced BRAF-mutated melanoma: navigating a shifting landscape

PeRioperative Optimization with Nutritional Supplements in Patients Undergoing GastRointEStinal Surgery for Cancer (PROGRESS): A Randomized Placebo-Controlled Feasibility Study Protocol (Preprint)

Background Postoperative morbidity following gastrointestinal tract major surgery ranges between 40% and 60%. Malnutrition, poor protein intake, and surgery-related impairment of the immune system and its function have been associated with postoperative infections. Supplemental perioperative nutrition may improve nutrition by increasing protein intake to influence cell-mediated immunity, thereby reducing the rate of postoperative infectious complications. Objective The primary objective of our trial is to determine the proportion of eligible patients randomized in an 18-month period. The primary feasibility outcome will be to (1) stop, main study not feasible: estimated proportion of randomized patients <40.0% (40/100); (2) continue with protocol modifications: estimated proportion of randomized patients 40.0% (40/100) to 59.0% (50/100); or (3) continue without modification: estimated proportion of randomized patients ≥60.0% (60/100). The secondary objectives are to evaluate compliance with the nutritional supplements and to estimate differences in postoperative complications, global health-related quality of life (QoL), and median length of hospital stay between the groups. Methods This is a double-blind randomized placebo-controlled feasibility trial. The intervention comprises three nutritional supplements: a protein isolate powder (ISOlution); immunomodulation (INergy-FLD), formulated liquid diet; and carbohydrate loading (PreCovery). Patients will consume 1 serving of the protein supplement per day from the randomization time up to 6 days before surgery (30 days in total). The immunomodulation, a solution that contains arginine, protein isolate, omega-6 fatty acids, and RNA, aims to attenuate excessive inflammatory responses and to replenish nutrients. This solution will be consumed as 3 doses per day for 5 days before and after surgery. Carbohydrate loading helps to reduce the stress from surgery by decreasing insulin resistance. Patients will have 2 servings the evening before surgery and 1 serving 2-3 hours before surgery. To be eligible, patients must have a resectable gastrointestinal cancer for which an elective operation is planned. Patients will be stratified according to nutritional status. The operation should occur within 4 weeks from enrollment. Results We expect to screen 165 eligible patients; 60.6% (100/165) of them will be randomized to either intervention or placebo. Assuming a two-sided alpha of .05, this will give us a 95% CI around the estimate of 53%-68%. A sample size of 50 per group will enable us to estimate the treatment effect and corresponding variance of the complication rate and QoL measures with adequate precision. The success is defined as the proportion of eligible patients randomized as ≥60.0% (60/100). Patients’ compliance is defined as an intake of at least 70% (41/58) sachets of the intervention volume. Conclusions The results will help to determine the feasibility of a larger randomized controlled trial to implement a perioperative nutritional supplement program for patients undergoing gastrointestinal surgery for cancer. Trial Registration ClinicalTrials.gov NCT03445260; https://clinicaltrials.gov/ct2/show/NCT03445260 (Archived by WebCite at http://www.webcitation.org/72CAmMzgP) International Registered Report Identifier (IRRID) PRR1-10.2196/10491

A new frontier in treatment of advanced melanoma: Redefining clinical management in the era of immune checkpoint inhibitors

ABSTRACT Immune checkpoint inhibitors have revolutionized treatment of advanced cutaneous melanoma. This group of novel therapeutic agents differs from other systemic treatments and has necessitated a new approach for several fundamental aspects of clinical practice in oncology. Marked differences in outcomes associated with immune checkpoint inhibitors compared with other systemic therapies has required a new paradigm for prognostication in the setting of advanced melanoma. Distinct patterns of tumor response have required new norms for disease monitoring. A unique spectrum of toxicity is associated with use of immune checkpoint inhibitors which can be severe and refractory. Patients and clinicians must be informed regarding immune-related adverse events, yet in the published literature, there is substantial variability in reporting. As immune checkpoint inhibitors gain a prominent role in cancer treatment, standardization of adverse event reporting will be vital to ensure validity of evidence and to promote safe clinical practice.