Comparison of baseline patient characteristics in Italian oncology drug monitoring registries and clinical trials: a real-world cross-sectional study.

Background: Generalizability of registrative clinical trials to real-world clinical practice is influenced by comparability of patients in the two settings. We compared characteristics of cancer patients in registrative trials with real-world clinical practice in Italy. Methods: Data on age, sex and performance status (PS) were derived from web-based monitoring registries developed by Italian Medicines Agency (AIFA) and corresponding registrative trials reported in the European Public Assessment Reports (EPAR) of European Medicines Agency (EMA). Weighted means were calculated in registries and trials and differences were described. Multivariate analysis was performed using Principal Component Analysis and Cluster Analysis. Findings: From January, 2013 to April, 2023, 419,461 unique pairs of patients and therapeutic indications were recorded in 129 AIFA registries. Within 140 related trials, 87,452 patients had been enrolled. Median age and rate of elderly (≥65 years old) patients were higher in monitoring registries than in clinical trials [mean difference of median age 5.3 years, p < 0.001; mean difference of elderly rate 17.17% (95% CI 1.06, 1.48)]. Overall, rate of female patients was not different between registries and trials [mean difference -0.55% (95% CI -1.06, -0.05)]. Mean rate of patients with deteriorated PS was low both in trials (3.1%) and in registries (4.3%) with a mean difference of 1.27% (95% CI 1.06, 1.48). Two clusters were identified with multivariate analysis: one including more registries (higher median age and elderly rate, lower female rate, higher rate of deteriorated patients), the other more trials (lower median age and elderly rate, higher female rate, lower rate of deteriorated patients). Interpretation: This study supports that cancer patients enrolled in trials do only partially represent those who have been treated in Italy in clinical practice. Inclusiveness of registrative trials should be increased to ensure generalizability of results to real-world population. Funding: Partially supported by Italian Ministry of Health.

Financial Toxicity and Health-Related Quality of Life Profile of Patients With Hematologic Malignancies Treated in a Universal Health Care System.

PURPOSE: We investigated the association of financial toxicity (FT) with the health-related quality of life (HRQoL) profile of patients with hematologic malignancies treated in a universal health care system. METHODS: We did a secondary analysis of six multicenter studies enrolling patients with hematologic malignancies. FT was evaluated using the financial difficulties item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Multivariable linear regression models were used to assess the mean differences in HRQoL scores between patients with or without FT, while adjusting for key potential confounding factors. We also examined the prevalence of clinically important problems and symptoms by the experience of FT, using established thresholds for the EORTC QLQ-C30. Multivariable binary logistic regression analysis was performed to explore the risk factors associated with FT. RESULTS: Overall, 1,847 patients were analyzed, of whom 441 (23.9%) reported FT. We observed statistically and clinically relevant worse scores for patients with FT compared with those without FT for all the EORTC QLQ-C30 scales. The three largest clinically relevant mean differences between patients with and without FT were observed in pain (∆ = 19.6 [95% CI, 15.7 to 23.5]; P < .001), social functioning (∆ = -18.9 [95% CI, -22.5 to -15.2]; P < .001), and role functioning (Δ = -17.7 [95% CI, -22.1 to -13.3]; P < .001). Patients with FT tended to report a higher prevalence of clinically important problems and symptoms across all EORTC QLQ-C30 scales. In the univariable and multivariable analyses, the presence of FT was associated with the presence of comorbidities, an Eastern Cooperative Oncology Group performance status ≥1, and not receiving a salary. CONCLUSION: Patients with hematologic malignancies treated in the setting of a universal health care system who experience FT have a worse HRQoL profile compared with those without FT.

Implementation of Precision Oncology in the National Healthcare System: A Statement Proposal Endorsed by Italian Scientific Societies.

PURPOSE: Precision oncology (PO) promises positive results for patients. To date, in Italy, the effort to implement PO has been made autonomously by regional health institutions in a top-down fashion. This approach is not very efficient and jeopardizes patients' equal access to PO. Similar outcomes have been recorded in other Western countries. We tested a method of collaboration among professionals, scientific societies, and government institutions to facilitate the delivery of PO innovation to patients' bedsides. METHOD: We designed an organizational research project on the basis of a bottom-up approach. We started by observing PO-related activities in five health care authorities (HCAs) in one Italian region. We then compared the issues that emerged with those of three additional HCAs in other Italian regions. Using the results of the initial observation and adopting validated multiple-step consensus methods, we finally derived 14 statements that were approved by the four main scientific societies of oncology and pathology at the national level. RESULTS: The 14 statements addressed the main issues linked to the implementation of PO in clinical practice. The strong professional consensus advocated for prompt adoption within the national healthcare system. CONCLUSIONS: The consensus on the statements that were obtained shows the importance of a synergistic effort among professionals, scientific societies, and health care institutions in defining homogeneous solutions for innovation implementation within the health care system.

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.

BACKGROUND: Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. METHODS: We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. FINDINGS: Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. INTERPRETATION: In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. FUNDING: The Canadian Cancer Society and Merck & Co.

Position paper of the Italian association of medical oncology on health disparities among transgender and gender-diverse people: the Assisi recommendations.

Transgender and gender-diverse individuals experience substantial health disparities across the cancer care continuum. Despite well recognized unique healthcare needs, there are barriers in accessing cancer prevention and treatment services, influenced by disadvantages in key social-economic determinants of health which result in worse clinical outcomes, as compared to the general population. The Italian Association of Medical Oncology (AIOM) acknowledges the critical relevance of this issue. The "Assisi Recommendations" here summarize the outcomes of the "AIOM Oncology Ethics Day" dedicated to gender differences in oncology and cancer care of transgender and gender-diverse people. The recommendations generated during a 2-day multidisciplinary discussion address the various aspects of cancer care experience of transgender and gender-diverse people. The promotion of research in this field, through the generation of new evidence and the collection of prospective data, has been identified as a priority action to mitigate these disparities. By acknowledging the challenges of cancer care in transgender and gender-diverse people and recognizing the need for dedicated policy and clinical recommendations, AIOM demonstrates its commitment to improving the health and well-being of all patients with cancer, regardless of their gender identity or any other personal or social circumstances, as part of health-for-all societal vision.

Cross-cultural adaptation of the PROFFIT Instrument to measure financial toxicity in people living with cancer within a UK population.

BACKGROUND: This study aimed to develop a British version of the Patient Reported Outcomes for Fighting Financial Toxicity of Cancer (PROFFIT): originally designed to measure financial toxicity in cancer for an Italian universal healthcare system. The instrument was carefully evaluated for crosscultural equivalence, face validity and practicality. METHODS: A systematic approach to cross-cultural adaptation was used, including forward translation, synthesis, backward translation, consolidation of translations with an expert committee, and cognitive interviews. As part of the cognitive interview process, 18 cancer patients completed a structured interview of 60-90 min in length. RESULTS: The translated and modified PROFFIT questionnaire demonstrated good psycho-linguistic properties, including high compliance (only one item was revised for clarity), high retrieval from memory, high decision-making processes, and high response processes. CONCLUSION: PROFFIT has been found to be functional and adaptable in a new social environment. The tool may be useful for tailoring interventions to address and measure financial hardships within the cancer population, which appear to be a current challenge for public health. POLICY SUMMARY: Even in universal healthcare systems, financial toxicity due to the increase in outof-pocket expenses poses a significant problem. The FT phenomenon warrants proper attention in the United Kingdom since it may negatively impact financial well-being, quality of life, psychosocial health, and treatment adherence.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study.

INTRODUCTION: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms. METHODS: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2). RESULTS: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007). CONCLUSIONS: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

Pitfalls in Oncogeriatrics.

An oncogeriatric interdisciplinary activity exists only in a minority of high-income countries, and it is almost absent in those with lower incomes. Considering topics, sessions, and tracks in the main meetings and conferences of the major Oncological Societies in Europe and worldwide, the USA excluded, little attention has thus far been paid to the problem of cancer in the elderly. Again, with the exception of the USA, the major cooperative groups, for example, the EORTC in Europe, have only dedicated marginal attention to the research of cancer in the elderly. Despite major shortcomings, professionals interested in geriatric oncology have taken a number of important initiatives to highlight the benefits of this particular activity, including the organization of an international society (Société Internationale de Oncogeriatrie, or SIOG). In spite of these efforts, the authors believe that the management of cancer in the older population is still encountering several important and generalized pitfalls. The main obstacle is the grossly inadequate number of geriatricians and clinical oncologists necessary to an integrated care of the ever-expanding aging population, but other hurdles have been reported. Additionally, the prejudice of ageism can lead to missing potential resources for the development of a generalized oncogeriatric approach.

Machine Learning Application Identifies Germline Markers of Hypertension in Patients With Ovarian Cancer Treated With Carboplatin, Taxane, and Bevacizumab.

Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management.

Biological and clinical impact of membrane EGFR expression in a subgroup of OC patients from the phase IV ovarian cancer MITO-16A/MANGO-OV2A trial.

BACKGROUND: Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. METHODS: EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. RESULTS: Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients' subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. CONCLUSIONS: Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients' stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. METHODS: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31). FINDINGS: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). INTERPRETATION: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. FUNDING: Pfizer.

Effect of bevacizumab in advanced low grade serous ovarian cancer: Data from the MITO 22 trial.

OBJECTIVE: The aim of the present analysis was to explore the efficacy of Bevacizumab (Bev) on survival outcome in advanced low grade serous ovarian cancer (LGSOC) both in first line and in recurrent setting. METHODS: In retrospective observational multicenter study, we described the outcome of LGSOC patients enrolled in the MITO 22 study and treated with chemotherapy (CT) with or without Bev. Patients receiving Bev in first-line or in recurrence were considered and compared with patients receiving CT alone (stage III and IV in first line; platinum based-CT in second line). Descriptive and survival analyses were performed for each group. RESULTS: Out of 128 patients included in MITO 22, 46 LGSOC patients receiving Bev in first line setting or at the time of first recurrence were identified. In first line, 30 patients received Bev + CT and 65 CT alone and the median PFS were 47.86 months (95% CI: 31.48 - NR) and 22.63 months (95% CI 15-39.24) (p-value 0.0392), respectively. In the recurrent setting, 16 patients who received Bev + CT were compared to 33 women treated with platinum-based CT alone. Median PFS were 37.1 months (95% CI: 13.42-40.56) and 11.22 months (95% CI: 8.26-15.63) (p-value 0.013), respectively. CONCLUSIONS: Our study suggests that Bev might be effective in LGSOC both at diagnosis and at the time of relapse. These data warrants further studies.

Cancer in Transgender and Gender-Diverse Persons: A Review.

Importance: Transgender and gender-diverse individuals face unique challenges, including barriers to health care access and inequities in treatment, that may influence cancer risk and outcomes. Observations: In this narrative review, a scoping review was conducted focusing on primary and secondary prevention and epidemiology of cancer, barriers to health care services, and health care practitioners' knowledge about specific issues pertaining to transgender and gender-diverse individuals. PubMed, the Cochrane Library, and Embase, were reviewed for citations from their inception to December 31, 2021. This review revealed that transgender and gender-diverse people had a high prevalence of tobacco consumption and alcohol use and high rates of infection with human papillomavirus (HPV) and HIV. Transgender and gender-diverse individuals were less likely to adhere to cancer screening programs and had a higher incidence of HIV- and HPV-associated cancers. Social and economic determinants seemed to drive these disparities in risk factors and outcomes. A lack of knowledge about gender minorities' health needs among health care practitioners was evidenced, and it represented a major hurdle to cancer prevention, care, and survivorship for transgender and gender-diverse individuals. Discrimination, discomfort caused by gender-labeled oncological services, stigma, and lack of cultural sensitivity of health care practitioners were other barriers met by transgender and gender-diverse persons in the oncology setting. Conclusions and Relevance: The findings suggest that transgender and gender-diverse peoples' needs in the cancer care continuum are not optimally addressed. Effective solutions are needed to offer the best care to every patient in a person-centric and gender diversity-sensitive environment.

Multinational Analysis of Estimated Health Care Costs Related to Extended-Interval Fixed Dosing of Checkpoint Inhibitors.

Importance: New dosing options for immune checkpoint inhibitors have recently been approved by the US Food and Drug Administration (FDA), including fixed dosing with extended intervals. Although the dose intensity appears the same, there is expected to be some waste with extended-interval dosing, as some drug remains in the bloodstream once a decision to stop treatment is made. The economic impact of extended-interval fixed dosing is unknown compared with standard-interval fixed dosing. Objective: To analyze the potential health care costs of using extended-interval fixed dosing instead of standard-interval fixed dosing. Design, Setting, and Participants: This economic evaluation used a pharmacoeconomic model to simulate 2 cohorts of patients with platinum-resistant metastatic urothelial cancer receiving pembrolizumab as second-line therapy at different dosing intervals using 2020 pricing data. Data were analyzed from 2020 to 2022. Exposures: The simulated patients received FDA-approved regimens of either 200 mg every 3 weeks or 400 mg every 6 weeks. Main Outcomes and Measures: The progression-free survival curve from the KEYNOTE-045 trial was used to estimate treatment duration. Drug, imaging, and administration costs were included in analyses. Sensitivity analyses were performed to assess how different imaging frequencies would affect the model results. The potential overall costs of using the 2 different dosing strategies were assessed. The base case was set in the US, while sensitivity analyses were set in several other countries. Results: In the base case analysis, dosing every 6 weeks instead of every 3 weeks resulted in an estimated 8.9% increase in pembrolizumab costs for the health care payer. Accounting for a decrease in infusion costs would result in an estimated net additional cost of $7483 per patient in the US (7.9% cost increase). In the US, this would amount to an increase of approximately $28 million annually for health care payers. Similar percentages in cost estimate increases were found for health care payers around the world, such as in Israel, where the net additional cost would be $5491 per patient. Conclusions and Relevance: This economic evaluation assessed and quantified the potential increased costs related to extended-interval fixed dosing of pembrolizumab. The model method could be applied to other diseases and other drugs for which there has been a movement toward extended-interval dosing. Results may differ in other diseases owing to differing disease courses and patient profiles.

Brief Report: Canadian Cancer Trials Group IND.227: A Phase 2 Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma (NCT02784171).

Immune checkpoint inhibitors have activity in mesothelioma. IND.227 was a phase 2 trial (120 patients planned) comparing progression-free survival of standard platinum and pemetrexed (CP) versus CP + pembrolizumab (pembro) versus pembro. Accrual to the pembro arm was discontinued on the basis of interim analysis (IA-16 wk disease control rate). CP + pembro was tolerable, with progression-free survival similar between arms and median survival and overall response rate higher than those of CP alone (19.8 mo [95% confidence interval or CI: 8.4-41.36] versus 8.9 mo [95% CI: 5.3-12.8] and 47% [95% CI: 24%-71%] versus 19% [95% CI: 5%-42%], respectively). The subsequent phase 3 trial has completed accrual; results are expected in 2023.

Patient-Reported Outcome Measures in Oncology Drugs Approved by the European Medicines Agency, 2017-2021.

This cross-sectional study investigates the use of patient-reported outcome measures in new marketing authorizations for oncology drugs approved by the European Medicines Agency (EMA) between 2017 and 2021.

Cultural adaptation of the Italian version of the Patient-Reported Outcomes Common Terminology Criteria for Adverse Event (PRO-CTCAE®).

INTRODUCTION: US National Cancer Institute's (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) is a library of 78 symptom terms and 124 items enabling patient reporting of symptomatic adverse events in cancer trials. This multicenter study used mixed methods to develop an Italian language version of this widely accepted measure, and describe the content validity and reliability in a diverse sample of Italian-speaking patients. METHODS: All PRO-CTCAE items were translated in accordance with international guidelines. Subsequently, the content validity of the PRO-CTCAE-Italian was explored and iteratively refined through cognitive debriefing interviews. Participants (n=96; 52% male; median age 64 years; 26% older adults; 18% lower educational attainment) completed a PRO-CTCAE survey and participated in a semi-structured interview to determine if the translation captured the concepts of the original English language PRO-CTCAE, and to evaluate comprehension, clarity and ease of judgement. Test-retest reliability of the finalized measure was explored in a second sample (n=135). RESULTS: Four rounds of cognitive debriefing interviews were conducted. The majority of PRO-CTCAE symptom terms, attributes and associated response choices were well-understood, and respondents found the items easy to judge. To improve comprehension and clarity, the symptom terms for nausea and pain were rephrased and retested in subsequent interview rounds. Test-retest reliability was excellent for 41/49 items (84%); the median intraclass correlation coefficient was 0.83 (range 0.64-0.94). DISCUSSION: Results support the semantic, conceptual and pragmatic equivalence of PRO-CTCAE-Italian to the original English version, and provide preliminary descriptive evidence of content validity and reliability.

Out-of-pocket costs sustained in the last 12 months by cancer patients: an Italian survey-based study on individual expenses between 2017 and 2018.

PURPOSE: Out of Pocket costs (OOP) sustained by cancer patients also in public NHS contribute to disease-related financial toxicity. Aim of the study was to investigate the amount and the types of OOP sustained by Italian cancer patients for care services. METHODS: A sample survey was conducted by FAVO in December 2017-June 2018, in 39 adhering hospitals and 1289 patients diagnosed from 1985 to 2018, by standardized questionnaire inquiring on: yearly expenditure by cancer service, age, year of diagnosis, disease phase, cancer site, sex, marital status, education, residence. Univariate and multivariable regression analyses were performed between OOP and each variable. Multilevel mixed-effects negative binomial regression was used to assess the combined effects of patients characteristics on the differences in acquiring health services. RESULTS: The yearly average OOP was 1841.81€, with the highest values for transports (359.34€) and for diagnostic examinations (259.82€). Significantly higher OOP were found in North and Centre than South and Islands (167.51 vs. 138.39). In the fully adjusted multivariable analysis, the variables significantly associated with higher than reference expenditure were: medium/high education (OR 1.22 [1.05-1.42], upper gastrointestinal tract cancer (OR 1.37 [1.06-1.77]), disease phase of treatments for cancer progression or pain therapy (OR 1.59 [1.30-1.93]). CONCLUSION: Italian cancer patients in 2018 sustained OOP quite similar to those measured in 2012 to supplement NHS services. The main component of the OOP costs were diagnostic examination and transportation. The NHS should pay attention to potentiate its ability to answer unmet needs of patients with advanced cancer who are the most fragile ones. IMPLICATIONS FOR CANCER SURVIVORS: Reinforcing the services where the main OOP expenses are located can help in promoting public health actions and reduce socio-economic needs that could compromise the receipt of optimal care along the whole disease course, from diagnosis to rehabilitation.

Systematic review of adoption, reporting and impact of health-related quality of life in phase III non-inferiority trials of systemic oncology treatments.

BACKGROUND: Quality of life (QoL) assessment and patient-reported outcomes appear to be crucial in the rationale and interpretation of non-inferiority (NI) trials. The aim of this study was to assess the inclusion of QoL among endpoints in phase III NI oncology trials and the relevance of QoL results in the reporting and interpretation of these studies. MATERIALS AND METHODS: By PubMed search and hand-search of 11 selected journals, we identified phase III NI trials in adult patients affected by solid tumours, published between 2012 and 2021. Trials were classified according to 4 NI strategies: (1) different drugs; (2) alternative drug administration routes; (3) shorter treatment duration; (4) "deintensification" of treatment schedule. Three main endpoints were: (1) the proportion of publications including QoL among endpoints; (2) the proportion of primary publications reporting QoL results; (3) the proportion of trials with available QoL results actually favoring the experimental treatment out of trials declaring NI. RESULTS: 106 publications were eligible. QoL was included among endpoints in 59 studies (55.7%), and QoL results were available in 40 primary publications (37.7%). In the 73 trials testing the NI of different drugs, QoL was included in 43 trials (58.9%) and QoL results were present in 31 publications (42.5%). Among the 74 trials formally demonstrating NI, only 19 trials (25.7%) had QoL results actually supporting the experimental treatment. CONCLUSIONS: In many NI trials in oncology, assessment and reporting of QoL are deficient. Furthermore, most trials formally claiming NI cannot count on QoL results actually supporting the experimental arm.

A multicenter randomized phase 4 trial comparing sodium picosulphate plus magnesium citrate vs. polyethylene glycol plus ascorbic acid for bowel preparation before colonoscopy. The PRECOL trial.

Background: Adequate bowel preparation before colonoscopy is crucial. Unfortunately, 25% of colonoscopies have inadequate bowel cleansing. From a patient perspective, bowel preparation is the main obstacle to colonoscopy. Several low-volume bowel preparations have been formulated to provide more tolerable purgative solutions without loss of efficacy. Objectives: Investigate efficacy, safety, and tolerability of Sodium Picosulphate plus Magnesium Citrate (SPMC) vs. Polyethylene Glycol plus Ascorbic Acid (PEG-ASC) solutions in patients undergoing diagnostic colonoscopy. Materials and methods: In this phase 4, randomized, multicenter, two-arm trial, adult outpatients received either SPMC or PEG-ASC for bowel preparation before colonoscopy. The primary aims were quality of bowel cleansing (primary endpoint scored according to Boston Bowel Preparation Scale) and patient acceptance (measured with six visual analogue scales). The study was open for treatment assignment and blinded for primary endpoint assessment. This was done independently with videotaped colonoscopies reviewed by two endoscopists unaware of study arms. A sample size of 525 patients was calculated to recognize a difference of 10% in the proportion of successes between the arms with a two-sided alpha error of 0.05 and 90% statistical power. Results: Overall 550 subjects (279 assigned to PEG-ASC and 271 assigned to SPMC) represented the analysis population. There was no statistically significant difference in success rate according to BBPS: 94.4% with PEG-ASC and 95.7% with SPMC (P = 0.49). Acceptance and willing to repeat colonoscopy were significantly better for SPMC with all the scales. Compliance was less than full in 6.6 and 9.9% of cases with PEG-ASC and SPMC, respectively (P = 0.17). Nausea and meteorism were significantly more bothersome with PEG-ASC than SPMC. There were no serious adverse events in either group. Conclusion: SPMC and PEG-ASC are not different in terms of efficacy, but SPMC is better tolerated than PEG-ASC. SPMC could be an alternative to low-volume PEG based purgative solutions for bowel preparation. Clinical trial registration: [ClinicalTrials.gov], Identifier [NCT01649674 and EudraCT 2011-000587-10].