First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.

BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC.

Designing a Patient-Friendly Website for Newly Diagnosed Cancer Patients with the Participatory Health Research Approach.

High-quality and user-friendly patient information material (PIM) is essential for understanding and accepting a new care programme. When optimising the PIM of the integrated, cross-sectoral psycho-oncological (isPO) care programme, the design of the fifth element of the patient information strategy-the patient-friendly website-was still pending. In this paper, the iterative design process of the patient-friendly isPO website is described. We applied the participatory health research (PHR) approach to enable high levels of participation of its respective end-users (e.g., cancer survivors), service providers, and experts. The design included six steps: (1) initiation, (2) planning, (3) initial idea exploration, (4) creation of a first working version, (5) three optimisation loops, and (6) dissemination. An exploratory mixed-methods design has been used. Qualitative data collection included document analysis, interviews, and participatory action research (PAR) loops with focus groups. Finally, the quality of the newly designed website was quantitatively assessed with the UPIM-Check, a user-friendly instrument for assessing and optimising PIM. The PHR approach was indispensable for the design of our needs-oriented, patient-friendly website. Participants' high levels of participation strongly contributed to the products' quality. The final descriptive statistical evaluation shows that the final website was rated very good on average by its end-users.

Participatory Development and Preliminary Psychometric Properties of the User-Friendly Patient Information Material Checklist (UPIM-Check).

The aims of this study were (1) to design a user-friendly instrument to assess and optimize patient information material (PIM), (2) to develop an English version, and (3) to test its psychometric properties. The instrument was needed to optimize the top-down developed PIM of the psycho-oncological care programme isPO. First, a literature-based PIM checklist was developed by a team of patient representatives, cancer care experts and professional researchers. Next, the checklist's reliability and validity were analysed by having cancer survivors assess the initial and optimized version of the isPO-leaflet. The User-friendly Patient Information Material Checklist (UPIM-Check), developed participatorily, was found to be effective for evaluating PIM. It uses a traffic light scale, and suggestions for improvement can be given for each criterion. Its reliability appeared to be excellent (α = 0.927). The optimized leaflet was rated significantly better than the initial one. The UPIM-Check is a reliable and valid instrument, which enables end-users (e.g., patients) to assess and optimize the quality of PIM according to scientific criteria and the needs of end-users. A bottom-up approach was essential for developing and validating the UPIM-Check. End-users constantly contributed with their specific knowledge. Thus, their position as co-researchers was significantly strengthened.