Prioritization and Resource Allocation in the Context of the COVID-19 Pandemic: Recommendations for Colorectal and Pancreatic Cancer in Germany.

In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.

Fast and label-free automated detection of microsatellite status in early colon cancer using artificial intelligence integrated infrared imaging.

PURPOSE: Microsatellite instability (MSI) due to mismatch repair (MMR) defects accounts for 15-20% of colon cancers (CC). MSI testing is currently standard of care in CC with immunohistochemistry of the four MMR proteins representing the gold standard. Instead, label-free quantum cascade laser (QCL) based infrared (IR) imaging combined with artificial intelligence (AI) may classify MSI/microsatellite stability (MSS) in unstained tissue sections user-independently and tissue preserving. METHODS: Paraffin-embedded unstained tissue sections of early CC from patients participating in the multicentre AIO ColoPredict Plus (CPP) 2.0 registry were analysed after dividing into three groups (training, test, and validation). IR images of tissue sections using QCL-IR microscopes were classified by AI (convolutional neural networks [CNN]) using a two-step approach. The first CNN (modified U-Net) detected areas of cancer while the second CNN (VGG-Net) classified MSI/MSS. End-points were area under receiver operating characteristic (AUROC) and area under precision recall curve (AUPRC). RESULTS: The cancer detection in the first step was based on 629 patients (train n = 273, test n = 138, and validation n = 218). Resulting classification AUROC was 1.0 for the validation dataset. The second step classifying MSI/MSS was performed on 547 patients (train n = 331, test n = 69, and validation n = 147) reaching AUROC and AUPRC of 0.9 and 0.74, respectively, for the validation cohort. CONCLUSION: Our novel label-free digital pathology approach accurately and rapidly classifies MSI vs. MSS. The tissue sections analysed were not processed leaving the sample unmodified for subsequent analyses. Our approach demonstrates an AI-based decision support tool potentially driving improved patient stratification and precision oncology in the future.

Longitudinal data on humoral response and neutralizing antibodies against SARS-CoV-2 Omicron BA.1 and subvariants BA.4/5 and BQ.1.1 after COVID-19 vaccination in cancer patients.

PURPOSE: The SARS-CoV-2 Omicron variant of concern (VOC) and subvariants like BQ.1.1 demonstrate immune evasive potential. Little is known about the efficacy of booster vaccinations regarding this VOC and subvariants in cancer patients. This study is among the first to provide data on neutralizing antibodies (nAb) against BQ.1.1. METHODS: Cancer patients at our center were prospectively enrolled between 01/2021 and 02/2022. Medical data and blood samples were collected at enrollment and before and after every SARS-CoV-2 vaccination, at 3 and 6 months. RESULTS: We analyzed 408 samples from 148 patients (41% female), mainly with solid tumors (85%) on active therapy (92%; 80% chemotherapy). SARS-CoV-2 IgG and nAb titers decreased over time, however, significantly increased following third vaccination (p < 0.0001). NAb (ND50) against Omicron BA.1 was minimal prior and increased significantly after the third vaccination (p < 0.0001). ND50 titers against BQ.1.1 after the third vaccination were significantly lower than against BA.1 and BA.4/5 (p < 0.0001) and undetectable in half of the patients (48%). Factors associated with impaired immune response were hematologic malignancies, B cell depleting therapy and higher age. Choice of vaccine, sex and treatment with chemo-/immunotherapy did not influence antibody response. Patients with breakthrough infections had significantly lower nAb titers after both 6 months (p < 0.001) and the third vaccination (p = 0.018). CONCLUSION: We present the first data on nAb against BQ.1.1 following the third vaccination in cancer patients. Our results highlight the threat that new emerging SARS-CoV-2 variants pose to cancer patients and support efforts to apply repeated vaccines. Since a considerable number of patients did not display an adequate immune response, continuing to exhibit caution remains reasonable.

Mental burden and moral distress among oncologists and oncology nurses in Germany during the third wave of the COVID-19 pandemic: a cross-sectional survey.

PURPOSE: There is evidence for mental burden and moral distress among healthcare workers during the pandemic. However, there is scarcity of analyses regarding possible correlations of mental burden and moral distress in this context. This study provides data to quantify mental burden and possible associations with moral distress among physicians and nurses working in oncology in Germany. METHODS: We conducted a cross-sectional online survey with physicians and nurses working in oncology in Germany between March and July 2021. Next to sociodemographic characteristics and working conditions, mental burden and moral distress were assessed using standardized instruments. Binary multivariate logistic regression using the enter method was performed in order to explore the relationship between mental burden and moral distress. RESULTS: 121 physicians and 125 nurses were included in the study. Prevalence of clinically relevant depressive symptoms, anxiety, somatic symptoms, burnout symptoms and moral distress was 19.2, 14.5, 12.7, 46.0 and 34.7% in physicians and 41.4, 24.0, 46.8, 46.6 and 60.0% in nurses respectively. Mental burden was significantly associated with moral distress, being female/diverse, younger age < 40 and increase in workload. Nurses who felt sufficiently protected from COVID-19 reported significantly less moral distress. CONCLUSION: To improve pandemic resilience, there is a need to ensure safe working environment including psychosocial support. Further evidence on risk and protective factors for moral distress is needed to be able to develop and implement strategies to protect healthcare workers within and beyond the pandemic.

Platinum-Based Chemotherapy in Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma: Summary of Evidence and Application in Clinical Practice.

BACKGROUND: Different therapeutic options are available for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Platinum-based multi-agent chemotherapy regimens, such as FOLFIRINOX, are important elements in the multidisciplinary management of PDAC. SUMMARY: At least one third of patients with metastatic PDAC are eligible for treatment with FOLFIRINOX. Eligibility criteria include good performance status and the absence of relevant comorbidities. However, chemotherapies can potentially be associated with serious adverse events, such as diarrhea or polyneuropathies. Here, we review relevant data from first-line, second-line, and maintenance therapy trials as well as real-world data. In addition, we address the management of possible adverse events. KEY MESSAGES: (1) Selection of a suitable treatment regime depends on patient performance status, comorbidities, and anticipated toxicity. (2) FOLFIRINOX is an appropriate treatment for patients up to 75 years of age with an ECOG PS of 0 or 1, without relevant comorbidities, normal or nearly normal bilirubin levels, and no significantly reduced DPD activity. (3) In particular, patients with germline BRCA1/2 (gBRCA1/2) or PALB2 mutations may benefit from first-line platinum-containing therapy. (4) Early and comprehensive testing of the patient's mutational status could support the first-line treatment decision-making.

The CIRCULATE Trial: Circulating Tumor DNA Based Decision for Adjuvant Treatment in Colon Cancer Stage II Evaluation (AIO-KRK-0217).

BACKGROUND: Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer. PATIENTS AND METHODS: CIRCULATE enrols patients with stage II microsatellite stable CRC in Germany (AIO) and Austria (ABCSG). Within the AIO, screening is supported by ColoPredict Plus 2.0, a molecular registry, and screening platform for interventional trials. Patient-specific mutations are centrally analysed by next generation sequencing in the resected primary tumour. A postoperative plasma sample is subsequently screened for the specific mutation(s). ctDNA positive (ctDNApos) patients are randomised (2:1) chemotherapy (capecitabine, oxaliplatin added an investigator's choice) or to follow-up (control group). ctDNA negative (ctDNAneg) patients are randomised (1:4) to be followed-up within CIRCULATE (control group) or outside the trial. Patients in the control group remain blinded to the ctDNA results. The primary objective is to compare disease free survival (DFS) of ctDNApos patients with chemotherapy or control. To demonstrate a treatment effect with a hazard ratio of 0.617 (3-year DFS rates 42.5% vs. 25%), 231 ctDNApos and estimated 2079 ctDNAneg patients are randomised. Secondary aims include to compare overall survival and DFS in the ctDNApos and ctDNAneg patient cohorts and ctDNA kinetics. CONCLUSION: The CIRCULATE trial may establish ctDNA for adjuvant treatment decision in stage II colon cancer - and with the secondary objectives - support a ctDNA guided follow up in colon cancer stage II and beyond.

A framework for falsifiable explanations of machine learning models with an application in computational pathology.

In recent years, deep learning has been the key driver of breakthrough developments in computational pathology and other image based approaches that support medical diagnosis and treatment. The underlying neural networks as inherent black boxes lack transparency and are often accompanied by approaches to explain their output. However, formally defining explainability has been a notorious unsolved riddle. Here, we introduce a hypothesis-based framework for falsifiable explanations of machine learning models. A falsifiable explanation is a hypothesis that connects an intermediate space induced by the model with the sample from which the data originate. We instantiate this framework in a computational pathology setting using hyperspectral infrared microscopy. The intermediate space is an activation map, which is trained with an inductive bias to localize tumor. An explanation is constituted by hypothesizing that activation corresponds to tumor and associated structures, which we validate by histological staining as an independent secondary experiment.

Causes of mortality in elderly UICC stage III colon cancer (CC) patients--Tumor-related death and competing risks from the German AIO colorectal study group Colopredict Plus (CPP) registry.

BACKGROUND: Colon cancer (CC) is a disease of elderly patients (pts.) with a median age of 73 years (yrs.). Lack of data about the effects of adjuvant chemotherapy (ACT) is caused by underrepresentation of this clinically relevant cohort in interventional trials. We analyzed real-world data from the German CPP registry with regard to a possible benefit of ACT in elderly (70+ yrs.) versus younger pts. (50 to <70 yrs.) taking cause-specific deaths into account. METHODS: We analyzed the effect of age and ACT on overall survival (OS) and cause-specific death of stage III pts. using Cox regression. RESULTS: In total, 1558 pts. were analyzed and follow-up was 24.6 months. 62.6% of the elderly received ACT whereas 91.1% of younger pts. (p < 0.001). Oxaliplatin combinations were significantly less often given to older than younger pts. (38.8% vs. 88.9%; p < 0.001). Mean Charlson comorbidity score was significantly lower in pts. that received ACT (0.61) than in those without ACT (1.16; p < 0.001). ACT was an independent positive prognostic factor for cancer-related death in elderly pts. even in pts. 75+ yrs. No significant difference in the effect of ACT could be observed between age groups (interaction: cancer-specific death HR = 1.7948, p = 0.1079; death of other cause HR = 0.7384, p = 0.6705). CONCLUSION: ACT was an independent positive prognostic factor for OS. There may be a cohort of elderly with less co-morbidities who benefit from ACT.