Determinants Affecting the Clinical Implementation of a Molecularly Informed Molecular Tumor Board Recommendation: Experience from a Tertiary Cancer Center.

Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.

Improving the Quality of Care for Cancer Patients through Oncological Second Opinions in a Comprehensive Cancer Center: Feasibility of Patient-Initiated Second Opinions through a Health-Insurance Service Point.

BACKGROUND: To improve the quality and cost-effectiveness of care, cancer patients can obtain a second medical opinion on their treatment. Validation of the diagnostic procedure (e.g., imaging), diagnosis, and treatment recommendation allows oncological therapy to be applied in a more targeted way, optimizing interdisciplinary care. This study describes patients who received second opinions at the Comprehensive Cancer Center for Erlangen-Nuremberg metropolitan area in Germany over a 6-year period, as well as the amount of time spent on second-opinion counseling. METHODS: This prospective, descriptive, single-center observational study included 584 male and female cancer patients undergoing gynecological, urologic, or general surgery who sought a second medical opinion. The extent to which the first opinion complied with standard guidelines was assessed solely descriptively. RESULTS: The first opinion was in accordance with the guidelines and complete in 54.5% of the patients, and guideline compliant but incomplete in 13.2%. The median time taken to form a second opinion was 225 min, and the cancer information service was contacted by patients an average of eight times. CONCLUSIONS: The initial opinion was guideline compliant and complete in every second case. Without a second opinion, the remaining patients would have been denied a guideline-compliant treatment recommendation. Obtaining a second opinion gives patients an opportunity to receive a guideline-compliant treatment recommendation and enables them to benefit from newer, individualized therapeutic approaches in clinical trials. Establishing patient-initiated second opinions via central contact points appears to be a feasible option for improving guideline compliance.

Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy.

BACKGROUND: Assessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit. PATIENTS AND METHODS: Gene expression of CD3Z, CD8A and CXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival. RESULTS: The gene expression signature of CXCL9, CD3Z and CD8A correlates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44-0.74; TCGA: ρ-range: 0.56-0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with 'inflamed high' tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort). CONCLUSION: The gene expression signature of CD3Z, CD8A and CXCL9 can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.

Long-Term Experience of Chemoradiotherapy Combined with Deep Regional Hyperthermia for Organ Preservation in High-Risk Bladder Cancer (Ta, Tis, T1, T2).

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). MATERIALS AND METHODS: Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0-1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4-6 weeks after treatment with TUR-BT. RESULTS: Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05-5.12; p = .037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88-8.00; p = .092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50-0.99; p = .045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18-0.58; p = .0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03-0.56; p = .006). Median follow-up was 71 months. The median number of RHT sessions was five. CONCLUSION: The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. IMPLICATIONS FOR PRACTICE: Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1-2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.

68Ga-PSMA-11 PET/CT derived quantitative volumetric tumor parameters for classification and evaluation of therapeutic response of bone metastases in prostate cancer patients.

BACKGROUND: To evaluate the role of 68Gallium prostate-specific membrane antigen-positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) derived quantitative volumetric tumor parameters in comparison with fully diagnostic conventional CT and serum-PSA levels for classification and evaluation of therapeutic response of bone metastases in patients with metastasized prostate cancer (PC). METHODS: A total of 177 men with biochemical recurrence of prostate cancer suffering from bone metastases underwent PET/CT with [68Ga] Ga-PSMA-HBED-CC (68Ga-PSMA-11). To calculate 68Ga-PSMA-11 PET quantitative volumetric tumor parameters including whole-body total-lesion PSMA (TL-PSMA), whole-body PSMA-tumor volume (PSMA-TV), as well as the established maximum standard uptake values (SUVmax) and mean standard uptake values (SUVmean), all 443 68Ga-PSMA-11-positive bone lesions in the field of view were assessed quantitatively. Quantitative volumetric tumor parameters were correlated with CT-derived volume and bone density measurements of metastatic bone lesions, serum prostate-specific antigen (PSA) levels, and Gleason Scores. In the 20 patients suffering from bone metastases who underwent 68Ga-PSMA-11 PET/CT before and after therapy, CT-derived volume and bone density measurements of metastatic lesions were compared to biochemical response determined by serum-PSA levels. RESULTS: In 177 patients, a total of 443 68Ga-PSMA-11 PET-positive bone lesions were detected. Of these, 50 lesions (11%) were only detectable on PET but not on conventional CT. PET-positive/CT-negative bone metastases demonstrated a significantly lower PSMA uptake compared to PET-positive/CT-positive bone lesions (p < 0.05). SUVmax, SUVmean, PSMA-TV, and TL-PSMA of bone metastases were significantly higher (p < 0.05) in patients with Gleason Scores > 7 compared to those with Gleason Scores ≤ 7. In the linear regression analysis, an association was determined between SUVmean, Gleason Scores, lesion classification, and serum-PSA levels but not for CT-derived bone density measurements. No significant correlation could be found between changes of bone density and CT-derived volume measurements of metastatic bone lesions and changes of serum-PSA levels (p > 0.05) before and after therapy, while a highly significant correlation was observed for changes of PSMA-TV, TL-PSMA, and serum-PSA levels (p < 0.001). CONCLUSION: Our results suggest that 68Ga-PSMA-11 PET/CT might be a valuable tool for the detection and follow-up of bone metastases in patients with metastasized prostate cancer. 68Ga-PSMA-11 PET-derived quantitative volumetric parameters demonstrated a highly significant correlation with changes of serum-PSA levels during the course of therapy. No such correlation could be determined for bone density measurements of metastatic bone lesions. Compared to the fully diagnostic CT scan, a significantly higher proportion of bone metastases was detected on 68Ga-PSMA-11 PET.

68Ga-PSMA-11 PET/CT-derived metabolic parameters for determination of whole-body tumor burden and treatment response in prostate cancer.

PURPOSE: We aimed at evaluating the role of 68Ga-PSMA-11 PET/CT-derived metabolic parameters for assessment of whole-body tumor burden and its capability to determine therapeutic response in patients with prostate cancer. METHODS: A total of 142 patients with biochemical recurrence of prostate cancer underwent PET/CT with [68Ga]Ga-PSMA-HBED-CC (68Ga-PSMA-11). Quantitative assessment of all 641 68Ga-PSMA-11-positive lesions in the field of view was performed to calculate PSMA-derived parameters, including whole-body PSMA tumor volume (PSMA-TV) and whole-body total lesion PSMA (TL-PSMA), as well as the established SUVmax and SUVmean values. All PET-derived parameters were tested for correlation with serum PSA levels and for association with Gleason scores. In 23 patients who underwent 68Ga-PSMA-11 PET/CT before and after therapy with either external beam radiation, androgen deprivation, or docetaxel chemotherapy, SUVmax and TL-PSMA were compared to radiographic response assessment of CT images based on RECIST 1.1 criteria and to biochemical response determined by changes of serum PSA levels. RESULTS: PSMA-TV and TL-PSMA demonstrated a significant correlation with serum PSA levels (P < 0.0001) and TL-PSMA was significantly different for different Gleason scores. The agreement rate between TL-PSMA derived from PET and biochemical response was 87% (95% confidence interval, 0.66-0.97; Cohen's κ = 0.78; P < 0.01) and, thus, higher than for SUVmax, which was 74% (95% CI, 0.52-0.90; κ = 0.55; P < 0.01). Furthermore, agreement with PSA was higher for TL-PSMA and SUVmax than for CT-based response evaluation. Discordant findings between PET and CT were most likely due to limitations of CT and RECIST in rating small lymph nodes as metastases, as well as bone involvement, which was sometimes not detectable in CT. CONCLUSION: 68Ga-PSMA-11 PET/CT-derived metabolic tumor parameters showed promising results for evaluation of treatment response. Especially, TL-PSMA demonstrated higher agreement rates with biochemical response compared to SUVmax. Larger, ideally prospective trials are needed to help to reveal the full potential of metabolic parameters derived from PET imaging with 68Ga-PSMA-11.

Analysis and classification of oncology activities on the way to workflow based single source documentation in clinical information systems.

BACKGROUND: Today, cancer documentation is still a tedious task involving many different information systems even within a single institution and it is rarely supported by appropriate documentation workflows. METHODS: In a comprehensive 14 step analysis we compiled diagnostic and therapeutic pathways for 13 cancer entities using a mixed approach of document analysis, workflow analysis, expert interviews, workflow modelling and feedback loops. These pathways were stepwise classified and categorized to create a final set of grouped pathways and workflows including electronic documentation forms. RESULTS: A total of 73 workflows for the 13 entities based on 82 paper documentation forms additionally to computer based documentation systems were compiled in a 724 page document comprising 130 figures, 94 tables and 23 tumour classifications as well as 12 follow-up tables. Stepwise classification made it possible to derive grouped diagnostic and therapeutic pathways for the three major classes - solid entities with surgical therapy - solid entities with surgical and additional therapeutic activities and - non-solid entities. For these classes it was possible to deduct common documentation workflows to support workflow-guided single-source documentation. CONCLUSIONS: Clinical documentation activities within a Comprehensive Cancer Center can likely be realized in a set of three documentation workflows with conditional branching in a modern workflow supporting clinical information system.

Risk stratification for locoregional recurrence after radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. METHODS: Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. RESULTS: After a median follow-up of 25 months (interquartile range 19-29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage ≥pT3 (HR 4.32, p < 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p < 0.001), the number of removed LNs <10 (HR 2.62, p < 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p < 0.001 for all), with a predictive accuracy of 85.6 %, respectively. CONCLUSIONS: The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials.

Workflows in cancer treatment and their influence upon clinical documentation.

To establish single source cancer documentation for a complete comprehensive cancer center CCC we performed a systematic analysis of diagnostic, therapeutic and documentation workflows for 13 cancer entities. Results suggest that we will need three types of clinical documentation to cover all cancer entities of the Erlangen CCC. We expect to have a workflow for solid entities with inpatient treatment, one for solid entities treated ambulatory and one for non solid cancer entities.

IT infrastructure components to support clinical care and translational research projects in a comprehensive cancer center.

This paper presents the concept of an integrated IT infrastructure framework established at the comprehensive cancer center at the University Hospital Erlangen. The framework is based on the single source concept where data from the electronic medical record are reused for clinical and translational research projects. The applicability of the approach is illustrated by two case studies from colon cancer and prostate cancer research projects.

Populating the i2b2 database with heterogeneous EMR data: a semantic network approach.

In an ongoing effort to share heterogeneous electronic medical record (EMR) data in an i2b2 instance between the University Hospitals Münster and Erlangen for joint cancer research projects, an ontology based system for the mapping of EMR data to a set of common data elements has been developed. The system translates the mappings into local SQL scripts, which are then used to extract, transform and load the facts data from each EMR into the i2b2 database. By using Semantic Web standards, it is the authors' goal to reuse the laboriously compiled "mapping knowledge" in future projects, such as a comprehensive cancer ontology or even a hospital-wide clinical ontology.