Single-arm studies involving patient-reported outcome data in oncology: a literature review on current practice

Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 recent publications of single-arm studies of cancer treatment involving PRO data for current practice on design, analysis, reporting, and interpretation. We further examined their handling of potential bias and how they informed decision-making. Most studies (97%) analyzed PROs without stating a predefined research hypothesis. Thirteen studies (22%) used a PRO as a (co)primary endpoint. Definitions of PRO objectives, study population, endpoints, and strategies of handling missing data varied widely. Twenty-three studies (38%) compared the PRO data to external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missingness and intercurrent events including death were seldom discussed. Most studies (85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies lacks standards, and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single arm studies

P53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis

Current therapy against colorectal cancer (CRC) is based on DNA-damaging agents that remain ineffective in a proportion of patients. Whether and how non-curative DNA damage-based treatment affects tumor cell behavior and patient outcome is primarily unstudied. Using CRC patient-derived organoids (PDO)s, we show that sublethal doses of chemotherapy (CT) does not select previously resistant tumor populations but induces a quiescent state specifically to TP53 wildtype (WT) cancer cells, which is linked to the acquisition of a YAP1-dependent fetal phenotype. Cells displaying this phenotype exhibit high tumor-initiating and metastatic activity. Nuclear YAP1 and fetal traits are present in a proportion of tumors at diagnosis and predict poor prognosis in patients carrying TP53 WT CRC tumors. We provide data indicating the higher efficacy of CT together with YAP1 inhibitors for eradication of therapy resistant TP53 WT cancer cells. Together these results identify fetal conversion as a useful biomarker for patient prognosis and therapy prescription. The failure of chemotherapy in colorectal cancer is currently unclear. Here, the authors show that upon sub-lethal dose of chemotherapy wild-type p53 colorectal cancers acquire a quiescence-like phenotype and a YAP-dependent fetal-like intestinal stem cell state associated with a higher metastatic activity and poor prognosis in patients

Realising the full potential of data-enabled trials in the UK : a call for action

Rationale: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile, and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely inelectronic healthcare records (EHR). Opportunities exist to utilise these in innovative ways to decrease duplication of effort, and speed trial recruitment, conduct and follow-up. Approach: The National Institute of Health Research (NIHR), Health Data Research UK (HDR UK) and Clinical Practice Research Datalink (CPRD) co-organised a national workshop to accelerate the agenda for “data-enabled clinical trials”. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation. Reflection: Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a “route map” to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution. Discussion: EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for post-marketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call. ambitious data-enabled trials at scale. There is the opportunity for the United Kingdom to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale

Adaptive designs for clinical trials which adjust for imbalances in prognostic factors

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk Rectal Cancer (EXPERT-C)

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met