Developing tumor-specific PRO-CTCAE item sets: analysis of a cross-sectional survey in three German outpatient cancer centers.

BACKGROUND: To include the patient perspective in the assessment of adverse events in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the US National Cancer Institute, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets for patients with breast cancer (BC), multiple myeloma (MM), and prostate cancer (PC). METHODS: The cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. RESULTS: 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms (fatigue, muscle pain, insomnia, joint pain, general pain, dizziness, shortness of breath, and swelling) were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by insomnia. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set, and decreased appetite in the MM item set. CONCLUSIONS: Individual PRO-CTCAE item sets for a German patient population were developed for the three tumor entities on the basis of patients' differences in symptom profiles and perceptions. The quality and psychometric criteria of the newly compiled item sets should be evaluated in validation studies.

[Diagnostics and treatment of clinically relevant paraneoplastic syndromes]. / Diagnostik und Therapie klinisch relevanter paraneoplastischer Syndrome.

Paraneoplastic syndromes (PS) are rare disorders with often complex clinical manifestations that occur in association with a tumor without being triggered by direct tumor invasion or compression. They arise from tumor secretions of hormones, peptides or cytokines or from immune cross-reactivity between malignant and healthy tissue. They are categorized into endocrine, neurological, dermatological, rheumatological, and hematological PS. The PS most commonly occurs in small cell lung carcinoma but also in association with other respiratory tract tumors, gynecological tumors, and hematological malignancies. The PS can precede a tumor diagnosis, therefore timely diagnosis can improve the prognosis of a malignant disease. The diagnostics are based on the clinical presentation as well as diagnostic methods depending on the underlying pathogenesis. The most important treatment approach involves the best possible treatment of the tumor and a targeted treatment is only sometimes possible. This review focuses on the clinically most frequently encountered PS.

Contribution of Synthetic Data Generation towards an Improved Patient Stratification in Palliative Care.

AI model development for synthetic data generation to improve Machine Learning (ML) methodologies is an integral part of research in Computer Science and is currently being transferred to related medical fields, such as Systems Medicine and Medical Informatics. In general, the idea of personalized decision-making support based on patient data has driven the motivation of researchers in the medical domain for more than a decade, but the overall sparsity and scarcity of data are still major limitations. This is in contrast to currently applied technology that allows us to generate and analyze patient data in diverse forms, such as tabular data on health records, medical images, genomics data, or even audio and video. One solution arising to overcome these data limitations in relation to medical records is the synthetic generation of tabular data based on real world data. Consequently, ML-assisted decision-support can be interpreted more conveniently, using more relevant patient data at hand. At a methodological level, several state-of-the-art ML algorithms generate and derive decisions from such data. However, there remain key issues that hinder a broad practical implementation in real-life clinical settings. In this review, we will give for the first time insights towards current perspectives and potential impacts of using synthetic data generation in palliative care screening because it is a challenging prime example of highly individualized, sparsely available patient information. Taken together, the reader will obtain initial starting points and suitable solutions relevant for generating and using synthetic data for ML-based screenings in palliative care and beyond.

Predicting unplanned hospital readmission in palliative outpatients (PRePP) - study protocol of a longitudinal, prospective study to identify informal caregiver-related and structural predictors.

BACKGROUND: Although the majority of German patients in a palliative state prefer to die at home, the actual place of death is most often a hospital. Unplanned hospital readmissions (UHA) not only contradict most patients' preferences but also increase the probability of an aggressive end-of-life treatment. As limited knowledge is available which factors contribute to an UHA, the PRePP-project aims to explore predictors related to informal caregivers (IC) as well as medical and structural factors. METHODS: This prospective, observational, mono-centric study will assess structural and medical factors as well as ICs' psychological burden throughout seven study visits. Starting in April 2021 it will consecutively include 240 patients and their respective IC if available. Standardized measures concerning ICs' Quality of Life (WHOQOL-BREF), psychological distress (NCCN-Distress Thermometer), anxiety (GAD-7) and depressiveness (PHQ-9) will be assessed. If participants prefer, assessment via phone, browser-based or paper-based will be conducted. Medical records will provide routinely assessed information concerning patient-related characteristics such as gender, age, duration of hospital stay and medical condition. Nurse-reported data will give information on whether hospitalization and death occurred unexpectedly. Data will be progressed pseudonymized. Multivariable regression models will help to identify predictors of the primary endpoint "unplanned hospital admissions". DISCUSSION: The PRePP-project is an important prerequisite for a clinical risk assessment of UHAs. Nevertheless, it faces several methodological challenges: as it is a single center study, representativity of results is limited while social desirability might be increased as the study is partly conducted by the treatment team. Furthermore, we anticipated an underrepresentation of highly burdened participants as they might refrain from participation. TRIAL REGISTRATION: This study was retrospectively registered 19 October 2021 at clinicaltrials.gov (NCT05082389). https://clinicaltrials.gov/ct2/show/NCT05082389.

Adding cetuximab to paclitaxel and carboplatin for first-line treatment of carcinoma of unknown primary (CUP): results of the Phase 2 AIO trial PACET-CUP.

BACKGROUND: Patients with carcinoma of unknown primary (CUP) have a dismal prognosis, even when treated with multi-agent chemotherapy. We hypothesised that adding the epidermal growth-factor receptor (EGFR) inhibitor cetuximab to standard first-line chemotherapy with paclitaxel and carboplatin would improve PFS and RR in unfavourable CUP. METHODS: This open-labelled, multicentre Phase 2 study included patients with unfavourable, untreated adeno- or undifferentiated CUP. Patients were randomised to receive either paclitaxel/carboplatin (group A) or paclitaxel/carboplatin plus cetuximab (group B) every 3 weeks for a maximum of 6 cycles followed by cetuximab maintenance in group B. The primary endpoint was PFS in the two groups. Secondary endpoints were RR, toxicity and overall survival (OS). RESULTS: One-hundred-and-fifty patients were randomised (group A = 72, group B = 78). The median PFS and OS for all patients were 3.8 and 8.1 months (95% confidence interval (CI): 2.9-4.8 and 6.8-9.5). There was no significant difference in PFS (3.7 vs 4.6 months, HR 0.98) or OS (8.1 vs 7.4, HR 1.1) between the two treatment groups. Response rate tended to be better for chemotherapy plus cetuximab compared to chemotherapy alone (22% vs 15%). Adverse events grade ≥3 were comparable between the two groups, except for significantly increased skin toxicity in the cetuximab arm. CONCLUSIONS: Cetuximab plus paclitaxel/carboplatin did not improve PFS, OS and RR in metastatic CUP compared to paclitaxel/carboplatin alone. Addition of cetuximab resulted in additional skin toxicity. CLINICAL TRIAL REGISTRATION: The study was registered at clinicaltrials.gov as NCT00894569.

Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer.

BACKGROUND: The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients. METHODS: In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee. RESULTS: From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months. CONCLUSIONS: The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2. TRIAL REGISTRATION: http://www.clinicaltrials.gov: NCT00422773.