A tailored phase I-specific patient-reported outcome (PRO) survey to capture the patient experience of symptomatic adverse events.

BACKGROUND: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. METHODS: Here, we describe the creation of a tailored survey based on the National Cancer Institute's PRO-CTCAE for collecting patients' perspectives on symptomatic adverse events in phase I trials in oncology. RESULTS: We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists' perspectives on symptoms of relevance. CONCLUSIONS: This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.

Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE.

BACKGROUND: Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients' reported experience of these toxicities using PRO-CTCAE. METHODS: Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses. RESULTS: Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either 'quite a bit' or 'very much', respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild-moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions. CONCLUSION: This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

BACKGROUND: The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. OBJECTIVE: The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. PATIENTS AND METHODS: Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. RESULTS: Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥ 10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). CONCLUSIONS: Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Uptake of BRCA1/BRCA2 predictive genetic testing in an Irish population is low: a missed opportunity.

INTRODUCTION: Predictive testing for BRCA1 or BRCA2 allows at-risk individuals to engage with appropriate screening and treatment services if a pathogenic mutation is identified. Previous studies have shown uptake of predictive testing to most commonly range between 20% and 40% (Table 2). This represents a missed cancer prevention opportunity. Possible explanations for this low uptake include lack of disclosure of at-risk status to relatives, lack of awareness of cancer genetics services, or patient preference. The goal of the current study was to investigate the uptake of BRCA1 or BRCA2 predictive testing in an Irish population. METHODS: We performed a multicentre, retrospective analysis of 63 pedigrees from two Irish tertiary referral hospitals over a five-year period (2012-2017). Family pedigrees were reviewed to identify at-risk family members eligible for predictive BRCA1 or BRCA2 mutation testing as per international guidelines, and testing rates were determined. RESULTS: A total of 1048 eligible individuals were identified, 318 (30.4%) proceeded to BRCA1 or BRCA2 germline testing including [215 (37.5%) females and 99 males (21.5%)]. Women were significantly more likely to test than men (T = 3.7, p < .0002). Uptake of testing was significant higher amongst first-degree relatives 45% (150/323) compared to 20% (50/258) amongst second degree relatives, and 10 % (33/317) amongst more distant relatives (F = 25.32, p < 0.00001). CONCLUSIONS: Uptake of BRCA1 OR BRCA2 mutation testing in Ireland is suboptimal, particularly amongst Irish males and distant relatives. Further research is needed to identify strategies which may improve uptake within current legal and ethical frameworks.

Bugs as drugs: The role of microbiome in cancer focusing on immunotherapeutics.

The human microbiome comprising microorganisms, their collective genomes and metabolic products has gained tremendous research interest in oncology, as multiple cohorts and case studies have demonstrated discernible interpatient differences in this ecosystem based on clinical variables including disease type, stage, diet, antibiotic usage, cancer treatments, therapeutic responses and toxicities. The modulation of the gut microbiome is the subject of many ongoing preclinical and clinical investigations, through the manipulation of diet, as well as the use of prebiotics, probiotics, specific antibiotics, fecal microbial transplantation, microbial consortia and stool substitutes. Standardization and quality control are needed to maximize the information being generated in this growing field, ranging from technical assays to measure microbiome composition, to methodological aspects in the analysis and reporting of results. Proof-of-mechanism and proof-of-concept clinical trials with appropriate controls are needed to confirm or refute the feasibility, safety and ultimately the clinical utility of human microbiome modulation in cancer patients.

Clinicopathologic factors that influence prognosis and survival outcomes in men with metastatic castration-resistant prostate cancer treated with Radium-223.

BACKGROUND: In men with metastatic castration-resistant prostate cancer (mCRPC) with primarily bone metastases, radium-223 (223 Ra) improves overall survival (OS). However, the selection of 223 Ra is not guided by specific validated clinicopathologic factors, and thus outcomes are heterogeneous. PATIENTS AND METHODS: This retrospective survival analysis was performed in men with mCRPC treated with 223 Ra at our cancer center. Demographics and disease characteristics were collected. OS was calculated using the Kaplan-Meier method (log-rank). The potential prognostic factors were determined using both univariable (UVA) and multivariable analysis (MVA) (Cox-regression) methods. RESULTS: In total, 150 patients with a median age of 74 years (52-93) received 223 Ra between May 2015 and July 2018, and 58% had 6-20 bone metastases. Ninety-four (63%) patients received >4 223 Ra doses, and 56 (37%) received ≤4. The following pre-treatment factors were analyzed (median [range]): eastern cooperative oncology group performance status (ECOG PS), (1 [0-3]); Albumin (ALB), (39 g/L [24-47]); alkaline phosphatase (ALP), (110 U/L [35-1633]); and prostate-specific antigen (PSA), (49 µg/L [0.83-7238]). The median OS for all patients was 14.5 months (95% CI: 11.2-18). These factors were associated with poor survival outcomes in UVA and MVA: ALB <35 g/L, ALP >150 U/L, ECOG PS 2-3, and PSA >80 µg/L. By assigning one point for each of these factors, a prognostic model was developed, wherein three distinct risk groups were identified: good, 0-1 (n = 103); intermediate, 2 (n = 30); and poor risk, 3-4 points (n = 17). The median OS was 19.4, 10.0, and 3.1 months, respectively (p < 0.001). CONCLUSIONS: Pre-treatment ALB, ALP, ECOG, and PSA, were significantly correlated with OS and could guide treatment selection for men with mCRPC by identifying those who are most or least likely to benefit from 223 Ra. Validation in an independent dataset is required prior to widespread clinical utilization.

Where youth matters-clinicopathologic characteristics and emerging trends in treatment and outcomes in young Irish women with breast cancer.

BACKGROUND: Young women with breast cancer (YWBC) represent 7-12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. METHODS: YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R® (V3.2.0). RESULTS: We identified 345 patients. Median age was 36 years (23-39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p < 0.001]). One hundred-seventy patients (49%) were ER + HER2-, 88 (25.5%) were HER2+, and 58 (16.8%) were triple negative. Eighty patients (23.2%) received neoadjuvant therapy. Pathological complete response rates were statistically similar between C1 and C2 [C1 1 (0.9%) vs C2 16 (6.8%) p = 0.1]. Distant relapse occurred in 59 (19%) patients. There was a higher relapse rate (RR) in C1 [27 (32.1%) vs. 32 (15.7%), p < 0.002). HER2+ and ER+ HER2- patients in C1 had higher RRs than C2. Median overall survival in patients with metastatic disease was 29 months (range 2-119 months). CONCLUSION: Locally advanced disease was more prevalent in YWBC. Mastectomy and ALNC rates were high and most received multimodal treatment. The extent of axillary surgery declined over time. Outcomes were unchanged in triple negative patients. These remain a priority for research.

Unusual Sites of High-Grade Neuroendocrine Carcinomas: A Case Series and Review of the Literature.

BACKGROUND Neuroendocrine tumors (NETs) encompass a diverse group of varying clinicopathological entities arising from cells of the endocrine and nervous systems. The presentation of these unique tumors can range from occult disease discovered incidentally to hyperactive, metastatic secretory tumors. NETs most commonly originate in the gastrointestinal and respiratory tract, although they may occur at any site in the body due to the wide distribution of neuroendocrine cells. Their classification system is complex and continues to evolve, and the current system uses histological grade in defining these subtypes. Neuroendocrine carcinomas (NECs), or high-grade, poorly-differentiated NETs, are the most aggressive subtype. Surgical resection remains the primary treatment modality and may be curative, thus early diagnosis is paramount. Management of advanced NETs remains both a diagnostic and therapeutic challenge; however, advances in our understanding of these unique neoplasms as well as an evolving classification system has led to the development of adjunctive therapeutic approaches aimed to minimize morbidity and improve patient outcomes. CASE REPORT We present 6 cases of unusual sites of high-grade neuroendocrine carcinomas involving the cervix, gallbladder, oesophagus, ovary, prostate, and urinary bladder. CONCLUSIONS Our case series highlights the heterogenous and aggressive nature of this subtype of NETs as well as their diagnostic and therapeutic difficulties. We also review the evolution of the NET classification system and its impact on the management of these malignancies.