Education modalities for serious illness communication training: A scoping review on the impact on clinician behavior and patient outcomes.

BACKGROUND: Several clinician training interventions have been developed in the past decade to address serious illness communication. While numerous studies report on clinician attitudes and confidence, little is reported on individual education modalities and their impact on actual behavior change and patient outcomes. AIM: To examine what is known about the education modalities used in serious illness communication training and their impact on clinician behaviors and patient outcomes. DESIGN: A scoping review using the Joanna Briggs Methods Manual for Scoping Reviews was conducted to examine studies measuring clinician behaviors or patient outcomes. DATA SOURCES: Ovid MEDLINE and EMBASE databases were searched for English-language studies published between January 2011 and March 2023. RESULTS: The search identified 1317 articles: 76 met inclusion criteria describing 64 unique interventions. Common education modalities used were: single workshop (n = 29), multiple workshops (n = 11), single workshop with coaching (n = 7), and multiple workshops with coaching (n = 5); though they were inconsistently structured. Studies reporting improved clinician skills tended to be in simulation settings with neither clinical practice nor patient outcomes explored. While some studies reported behavior changes or improved patient outcomes, they did not necessarily confirm improvements in clinician skills. As multiple modalities were commonly used and often embedded within quality improvement initiatives, the impact of individual modalities could not be determined. CONCLUSION: This scoping review of serious illness communication interventions found heterogeneity among education modalities used and limited evidence supporting their effectiveness in impacting patient-centered outcomes and long-term clinician skill acquisition. Well-defined educational modalities and consistent measures of behavior change and standard patient-centered outcomes are needed.

Outcome measures in palliative care training interventions: a systematic review of trial-based studies.

BACKGROUND: The ability of health care clinicians to offer a palliative approach to care to their patients with progressive, life-limiting illness has become critical as demand for these services increases. Numerous training initiatives exist to assist clinicians who are not palliative care specialists in the development of palliative care skills, however there is little consensus on how to best measure the effectiveness of these education programs. We conducted a systematic review of palliative care training intervention trials to examine the outcomes measures used. METHODS: We searched MEDLINE, CINAHL, PsycINFO, Embase, HealthSTAR, and five trial registries for studies and protocols published since 2000. Eligible studies were trials assessing palliative care training for clinicians. Interventions had to address at least two of six palliative care-related domains, based on the National Consensus Project: identification or assessment; illness understanding; symptom management; decision making (e.g., advance care planning); coping (patient and caregivers); and referral (coordination/care planning). Each article was reviewed independently by a minimum of two reviewers for inclusion and extraction of relevant data. RESULTS: Of 1,383 articles reviewed, 36 studies met the inclusion criteria, 16 (44%) of which focused on palliative care communication skills. Among all the trials, 190 different measures were reported. Only 11 validated measures were used in at least 2 studies, including the End-of-Life Professional Caregiver Survey (EPCS) for clinicians and the Quality of Dying and Death Questionnaire (QODD) for caregivers. Clinician and patient/caregiver reported outcomes were measured in 75% and 42% of studies, respectively. Half of the trials employed a study-created questionnaire. Data from administrative (n=14) and/or qualitative (n=7) sources were also used. Nine studies, almost exclusively those with a communication skills focus, assessed clinician interactions as an outcome. CONCLUSIONS: We found considerable diversity in outcomes among the trials reviewed. Further examination of the outcomes used in the broader literature and development of these measures is needed. This will assist towards establishing meaningful and consistent metrics for assessing the impact of palliative care education, to inform evidence-based scaling of effective programs.

Increasing palliative care capacity in primary care: study protocol of a cluster randomized controlled trial of the CAPACITI training program.

BACKGROUND: Primary care providers play a critical role in providing early palliative care to their patients. Despite the availability of clinical education on best practices in palliative care, primary care providers often lack practical guidance to help them operationalize this approach in practice. CAPACITI is a virtual training program aimed at providing practical tips, strategies, and action plans to provide an early palliative approach to care. The entire program consists of 12 sessions (1 h each), divided evenly across three modules: (1) Identify and Assess; (2) Enhance Communication Skills; (3) Coordinate for Ongoing Care. We report the protocol for our planned evaluation of CAPACITI on its effectiveness in helping primary care providers increase their identification of patients requiring a palliative approach to care and to strengthen other core competencies. METHODS: A cluster randomized controlled trial evaluating two modes of CAPACITI program delivery: 1) self-directed learning, consisting of online access to program materials; and 2) facilitated learning, which also includes live webinars where the online materials are presented and discussed. The primary outcomes are 1) percent of patients identified as requiring palliative care (PC), 2) timing of first initiation of PC, and self-reported PC competency (EPCS tool). Secondary outcomes include self-reported confidence in PC, practice change, and team collaboration (AITCS-II tool), as well as qualitative interviews. Covariates that will be examined are readiness for change (ORCA tool), learning preference, and team size. Primary care teams representing interdisciplinary providers, including physicians, nurse practitioners, registered nurses, care coordinators, and allied health professionals will be recruited from across Canada. The completion of all three modules is expected to take participating teams a total of six months. DISCUSSION: CAPACITI is a national trial aimed at behavior change in primary care providers. This research will help inform future palliative care educational initiatives for generalist health care providers. Specifically, our findings will examine the effectiveness of the two models of education delivery and the participant experience associated with each modality. TRIAL REGISTRATION: ClinicalTrials.gov NCT05120154.

The Serious Illness Care Program in Oncology: Evidence, Real-World Implementation and Ongoing Barriers.

The Serious Illness Care Program (SICP), designed by Ariadne Labs, is a multicomponent intervention to improve conversations about values and goals for patients with a life-limiting illness. In oncology, implementation of the SICP achieved more, earlier, and better-quality conversations and reduced anxiety and depression among patients with advanced cancer. In this commentary, we describe the SICP, including results from the cluster-randomized trial, provide examples of real-world implementation of this program, and highlight ongoing challenges and barriers that are preventing widespread adoption of this intervention into routine practice. For the SICP to be successfully embedded into routine patient care, it will require significant effort, including ongoing leadership support and training opportunities, champions from all sectors of the interdisciplinary team, and adaptation of the program to a wider range of patients. Future research should also investigate how early conversations can be translated into personalized care plans for patients.

Role of Adjuvant Therapy in Esophageal Cancer Patients After Neoadjuvant Therapy and Esophagectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection to determine whether additional adjuvant therapy is associated with improved survival outcomes. SUMMARY BACKGROUND DATA: Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal cancer, whereas adjuvant therapy is typically employed for patients with residual disease. However, the role of adjuvant therapy after a curative resection is still uncertain. METHODS: MEDLINE, EMBASE, and CENTRAL databases were searched for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation was used to assess the certainty of evidence. RESULTS: Ten studies involving 6462 patients were included. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant decrease in mortality by 48% at 1 year (Risk Ratio (RR) 0.52, 95% confidence interval [CI] 0.41-0.65, P < 0.001, moderate certainty). This reduction in mortality was carried through to 5-year follow-up (RR 0.91, 95% CI 0.86-0.96, P < 0.001, moderate certainty). The difference between the adjuvant therapy and the control group was uncertain regarding the secondary outcomes. CONCLUSION: Adjuvant therapy after neoadjuvant treatment and esophagectomy with negative resection margins provide an improved OS at 1 and 5 years with moderate to high certainty of evidence, but the benefit for disease-free survival and locoregional/distal recurrence remain uncertain due to limited reporting of these outcomes.

Concurrent use of statins and neoadjuvant chemoradiotherapy for rectal cancer: a systematic review and meta-analysis.

PURPOSE: Statins are used primarily in patients with cardiovascular disease. More recently, they have demonstrated benefit in oncology patients. In vitro models have shown decreased rectal tumor cell viability in cells receiving chemoradiation and statin therapy. In vivo models have been less clear. This study aims to elucidate the impact of concurrent use of statins on the efficacy of neoadjuvant therapy for rectal cancer. METHODS: Search of Medline, EMBASE, and CENTRAL was performed. Articles were included if they reported complete pathological response (pCR), long-term oncologic outcomes, or chemoradiotherapy-induced toxicity in patients with rectal cancer receiving concurrent statin and neoadjuvant therapy. A pairwise meta-analyses was performed using inverse variance random effects. RESULTS: From 1564 citations, six studies with 726 patients on statin therapy (24.5% female, age: 63.6 years) and 1863 patients not on statin therapy (35.6% female, age: 60.9 years) were included. There was no significant difference in pCR rate between patients on statin therapy and patients not on statin therapy (RR 1.23, 95%CI 0.98-1.54, p = 0.08). Similarly, no difference existed between groups in long-term oncologic outcomes (5-year overall survival: RR 1.03, 95%CI 0.86-1.24, p = 0.75; 5-year disease-free survival: RR 1.04, 95%CI 0.85-1.26, p = 0.73). Chemoradiotherapy-induced toxicities were similar between groups. CONCLUSION: The concurrent use of statin and neoadjuvant therapy did not significantly impact short- or long-term oncologic outcomes in patients with rectal cancer. Yet, despite pooling of data, this study remained inadequately powered. Larger, prospective studies are required to further elucidate the impact of statins on patients undergoing neoadjuvant therapy for rectal cancer.

Radiotherapy alone versus chemoradiotherapy for stage I anal squamous cell carcinoma: a systematic review and meta-analysis.

PURPOSE: Patients with stage I anal squamous cell carcinoma (SCC) have been underrepresented in landmark trials showing superiority of chemoradiotherapy over radiotherapy for definitive treatment. This review aims to elucidate whether definitive treatment with radiotherapy versus chemoradiotherapy is associated with differences in survival and treatment-related toxicity outcomes in patients with stage I anal SCC. METHODS: Medline, EMBASE, and CENTRAL were searched as of November 2020 to identify studies comparing outcomes of radiotherapy versus chemoradiotherapy for non-operative treatment of patients with stage I anal SCC. The primary outcomes were 5-year overall survival and 5-year disease-free survival. The secondary outcome was treatment-related toxicities. A pairwise meta-analysis was performed using an inverse-variance random-effects model. RESULTS: From 2174 citations, 5 retrospective studies with 415 patients treated with radiotherapy and 3784 patients treated with chemoradiotherapy were included. Patients treated with chemoradiotherapy had an increased 5-year overall survival (RR 1.18, 95% CI 1.10-1.26, p < 0.00001, I2 = 0%) but no significant difference in 5-year disease-free survival (RR 1.01, 95% CI 0.92-1.11, p = 0.87, I2 = 0%). Treatment-related toxicities could not be meta-analyzed due to heterogeneity. Limited data from individual studies suggested an increased frequency of select toxicities with chemoradiotherapy. CONCLUSION: Radiotherapy may be an appropriate alternative to chemoradiotherapy for patients with stage I anal SCC who may be unable to tolerate chemotherapy-related toxicity; however, chemoradiotherapy remains the gold standard. Larger prospective studies comparing strategies for this select patient population are needed to clarify whether treatment can be de-escalated.

Evaluation of a novel strategy to implement exercise evidence into clinical practice in breast cancer care: protocol for the NEXT-BRCA randomised controlled trial.

INTRODUCTION: The burden of breast cancer in Canada is steadily growing. More women are surviving breast cancer, yet, survivors live with side effects for years after treatments have ended. The benefits of exercise for women with breast cancer are well established and include improvement in treatment-related physical and emotional side effects. Despite these benefits, few survivors meet exercise guidelines. Exercise programmes are needed within the cancer institution in Canada to bridge the current knowledge to practice gap. The purpose of this study is to test the effects of a novel implementation strategy that includes institution-based exercise plus self-management (SM) or SM alone versus usual care in improving exercise level, quality of life, aerobic capacity, muscle strength and use of healthcare services over 12 months for women with breast cancer receiving chemotherapy. METHODS AND ANALYSIS: Participants: Women with stages I-III breast cancer undergoing chemotherapy. Intervention: Group 1: institution-based exercise and SM (8 exercise sessions plus 8 SM modules); Group 2: SM alone; Group 3: usual care. Outcomes: The primary effectiveness outcome is minutes per week of moderate to vigorous physical activity. Secondary outcomes include quality of life, aerobic capacity, muscle strength, and use of healthcare services. Randomisation: Participants will be randomised (1:1:1) to one of the three groups by a blinded statistician and will be stratified based on age of participant (<40, 40-60, and >60 years). Statistical analysis: Outcomes will be measured at baseline, post-intervention, 6-month and 12-month follow-up using an analysis of covariance to test changes between groups over time adjusted for age. ETHICS AND DISSEMINATION: This study addresses a long-standing need to help women with breast cancer undergoing chemotherapy become and stay more active by implementing novel rehabilitation strategies into real-world practice. This is vital in order for this population to minimise the lingering side effects of treatment, improve function and quality of life and prevent cancer recurrence. TRIAL REGISTRATION NUMBER: The study protocol (v1: July 2020) has been registered on ClinicalTrials.gov (NCT04109274).

Virtual Cancer Care During the COVID-19 Pandemic and Beyond: A Call for Evaluation.

The interplay of virtual care and cancer care in the context of the COVID-19 pandemic is unique and unprecedented. Patients with cancer are at increased risk of SARS-CoV-2 infection and have worse outcomes than patients with COVID-19 who do not have cancer. Virtual care has been introduced quickly and extemporaneously in cancer treatment centers worldwide to maintain COVID-19-free zones. The outbreak of COVID-19 in a cancer center could have devastating consequences. The virtual care intervention that was first used in our cancer center, as well as many others, was a landline telephone in an office or clinic that connected a clinician with a patient. There is a lack of virtual care evaluation from the perspectives of patients and oncology health care providers. A number of factors for assessing oncology care delivered through a virtual care intervention have been described, including patient rapport, frailty, delicate conversations, team-based care, resident education, patient safety, technical effectiveness, privacy, operational effectiveness, and resource utilization. These factors are organized according to the National Quality Forum framework for the assessment of telehealth in oncology. This includes the following 4 domains of assessing outcomes: experience, access to care, effectiveness, and financial impact or cost. In terms of virtual care and oncology, the pandemic has opened the door to change. The lessons learned during the initial period of the pandemic have given rise to opportunities for the evolution of long-term virtual care. The opportunity to evaluate and improve virtual care should be seized upon.

Health Utility Book (HUB)-Cancer: Protocol for a Systematic Literature Review of Health State Utility Values in Cancer.

Background. Treatment options in oncology are rapidly advancing, and public payer systems are increasingly under pressure to adopt new but expensive cancer treatments. Cost-utility analyses (CUAs) are used to estimate the relative costs and effects of competing interventions, where health outcomes are measured using quality-adjusted life years (QALYs). Health state utility values (HSUVs) are used to reflect health-related quality of life or health status in the calculation of QALYs. To support reimbursement agencies in the appraisal of oncology drug submissions, which typically include a CUA component, we have proposed a systematic literature review of published HSUV estimates in the field of oncology. Methods. The following databases will be searched: MEDLINE, EMBASE, EconLit, and CINAHL. A team of reviewers, working independently and in duplicate, will evaluate abstracts and full-text publications for eligibility against broad inclusion criteria. Studies using a direct, indirect, or combination approach to eliciting preferences related to cancer or cancer treatments are eligible. Data extraction will capture details of study methodology, participants, health states, and corresponding HSUVs. We will summarize our findings with descriptive analyses at this stage. A pilot review in thyroid cancer is presented to illustrate the proposed methods. Discussion. This systematic review will generate a comprehensive summary of the oncology HSUV literature. As a component of the Health Utility Book (HUB) project, we anticipate that this work will assist both health economic modelers as well as critical reviewers in the development and appraisal of CUAs in oncology.

Colorectal cancer in adolescents and young adults: Defining a growing threat.

Colorectal cancer (CRC) incidence is rising among adolescents and young adults (AYAs), with the greatest increase occurring in distal colon and rectal cancers. Reasons for this striking trend are not well understood. Genetically linked cases of CRC occur in the context of familial conditions such as Lynch Syndrome, but most AYA cases of CRC are sporadic. Unique biology is suggested, yet limited information is available regarding the molecular underpinnings of CRC in this age group. Young patients are more likely to experience delays in diagnosis and to present with advanced-stage disease; yet, prognosis by stage is comparable between younger and older adults. Treatment paradigms are based on evidence reflecting the older adult population. Given the concerning rise in CRC rates among AYAs, there is urgent need for further research into the role of screening from a younger age, biology of disease, and optimal therapies in this age group.

Toward a Centralized, Systematic Approach to the Identification, Appraisal, and Use of Health State Utility Values for Reimbursement Decision Making: Introducing the Health Utility Book (HUB).

Cost-utility analysis (CUA) is a widely recommended form of health economic evaluation worldwide. The outcome measure in CUA is quality-adjusted life-years (QALYs), which are calculated using health state utility values (HSUVs) and corresponding life-years. Therefore, HSUVs play a significant role in determining cost-effectiveness. Formal adoption and endorsement of CUAs by reimbursement authorities motivates methodological advancement in HSUV measurement and application. A large body of evidence exploring various methods in measuring HSUVs has accumulated, imposing challenges for investigators in identifying and applying HSUVs to CUAs. First, large variations in HSUVs between studies are often reported, and these may lead to different cost-effectiveness conclusions. Second, issues concerning the quality of studies that generate HSUVs are increasingly highlighted in the literature. This issue is compounded by the limited published guidance and methodological standards for assessing the quality of these studies. Third, reimbursement decision making is a context-specific process. Therefore, while an HSUV study may be of high quality, it is not necessarily appropriate for use in all reimbursement jurisdictions. To address these issues, by promoting a systematic approach to study identification, critical appraisal, and appropriate use, we are developing the Health Utility Book (HUB). The HUB consists of an HSUV registry, a quality assessment tool for health utility studies, and a checklist for interpreting their use in CUAs. We anticipate that the HUB will make a timely and important contribution to the rigorous conduct and proper use of health utility studies for reimbursement decision making. In this way, health care resource allocation informed by HSUVs may reflect the preferences of the public, improve health outcomes of patients, and maintain the efficiency of health care systems.

Network meta-analysis of therapies for previously untreated advanced BRAF-mutated melanoma.

BACKGROUND: The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level. METHODS: The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fixed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio. RESULTS: Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine). CONCLUSIONS AND RELEVANCE: The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.

Adjuvant Chemotherapy With or Without Biologics Including Antiangiogenics and Monoclonal Antibodies Targeting EGFR and EpCAM in Colorectal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Adjuvant therapy for early-stage colorectal cancer improves survival. Biologic agents have shown promise as adjuncts to chemotherapy in metastatic colon cancer, but the effect on earlier stage cancer remains unclear. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of the additive effect of biologic agents to adjuvant chemotherapy on survival in colorectal cancer (all comers and subpopulations defined by microsatellite instability, BRAF and KRAS status, and stage). Only randomized controlled trials published between 2002 and 2017 in MEDLINE, EMBASE, and CENTRAL were included. The control arm: chemotherapy alone, the intervention arm: chemotherapy with biologic agents. OUTCOMES: overall survival (OS) and disease-free survival. RESULTS: Six trials including 10,754 patients were included. OS (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.15-3.03) and disease-free survival (HR 2.54, 95% CI 2.25-2.87) were significantly worse in the intervention arm. High heterogeneity was explained by subgroup analysis of different biologic agents (bevacizumab versus others); however, results still showed harm in the intervention arm across subgroups. Bevacizumab was associated with improved OS in patients with microsatellite instability (HR 0.58, 95% CI 0.36-0.92); this was the only indication of benefit for a biomarker-defined subpopulation. Analyses by tumor stage failed to demonstrate advantage with use of a biologic agent; however, it explained heterogeneity. CONCLUSIONS: The addition of biologic agents to adjuvant chemotherapy in the treatment of high-risk stage II and III colorectal cancer is associated with worse survival outcomes. The only subgroup of patients that may benefit from the addition of bevacizumab to adjuvant chemotherapy is those with microsatellite unstable tumors.

Perioperative Optimization With Nutritional Supplements in Patients Undergoing Gastrointestinal Surgery for Cancer (PROGRESS): Protocol for a Feasibility Randomized Controlled Trial.

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.

Does the Addition of Biologic Agents to Chemotherapy in Patients with Unresectable Colorectal Cancer Metastases Result in a Higher Proportion of Patients Undergoing Resection? A Systematic Review and Meta-analysis.

BACKGROUND: Surgical resection provides the best opportunity for cure for metastatic colorectal cancer. Whether addition of a biologic agent to chemotherapy improves the rate of conversion from unresectable to resectable disease remains uncertain. We carried out a systematic review of the literature and meta-analysis to define the impact of biologic agents on resection. METHODS: We searched Medline, Embase, CENTRAL, and PubMed for randomized controlled trials published up until April 2017 comparing chemotherapy and biologics (intervention) vs. chemotherapy alone (control) in treatment-naïve patients with unresectable metastatic colorectal cancer. Study selection, data abstraction, risk of bias, and quality of evidence assessment were performed in duplicate. Random-effects meta-analysis was used to estimate the pooled odds ratio (OR) for resection rate and corresponding confidence interval (CI). RESULTS: Nine studies, including a total of 4345 patients, were analyzed. Seven studies assessed epithelial growth factor receptor (EGFR)-directed monoclonal antibodies, and two used antiangiogenic agents. The addition of a biologic agent to chemotherapy was associated with higher resection rate (OR 1.47, 95% CI 1.07-2.02; resection rate 8.4 vs. 6.1%). Subgroup analysis based on mechanism of action of drugs showed benefit for resection rate only with EGFR-directed agents (OR 1.70, 95% CI 1.10-2.64). Heterogeneity among studies was low (I 2  = 34%). CONCLUSIONS: The addition of biologic agents to systemic chemotherapy in patients with initially unresectable metastatic colorectal cancer improved resection rate. The optimal biologic agent for this outcome cannot yet be determined.

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

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.

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.