Cancer care in German centers of excellence during the first 2 years of the COVID-19 pandemic.

PURPOSE: An increasing number of international studies demonstrate serious negative effects of the COVID-19 pandemic on the timely diagnosis of cancer and on cancer treatment. Our study aimed to quantitatively and qualitatively evaluate the capacities of German Comprehensive Cancer Centers (CCCs) in different areas of complex oncology care during the first 2 years of the COVID-19 pandemic. METHODS: Prospective panel survey over 23 rounds among 18 CCCs in Germany between March 2020 and June 2022. RESULTS: The COVID-19 pandemic substantially affected the oncological care system in Germany during the first 2 years. Persistent limitations of care in CCCs primarily affected follow-up (- 21%) and psycho-oncologic care (- 12%), but also tumor surgery (- 9%). Substantial limitations were also reported for all other areas of multidisciplinary oncological care. CONCLUSIONS: This study documents the limitations of oncological care during the COVID-19 pandemic and highlights the need to develop strategies to avoid similar limitations in the future.

Liquid Biopsy in Colorectal Cancer: Quo Vadis? Implementation of Liquid Biopsies in Routine Clinical Patient Care in Two German Comprehensive Cancer Centers.

Objectives: The use of liquid biopsies (LB) in patients with solid malignancies enables comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) and has the potential to guide therapy stratification and support disease monitoring. To examine clinical uptake of LB in a real-world setting, LB implementation was analyzed at two German cancer centers (LMU Munich and Charité - Universitätsmedizin Berlin) between 2017 and 2021, with focus on colorectal cancer (CRC) patients. Methods: In this retrospective analysis, all patients who received a LB between January 2017 and December 2021 as part of routine clinical management were included. To provide adequate context, we collected disease characteristics and technical specifications of the LB methods applied. Additionally, we examined the concordance of RAS status in tumor tissue and LB. Finally, we discuss the potential of LB as a diagnostic tool to drive personalized treatment in CRC patients and how to implement LB in clinical routine. Results: In total, our cohort included 86 CRC patients and 161 LB conducted in these patients between 2017 and 2021. In 59 patients, comparison between tissue-based and liquid-based molecular diagnostics, revealed a divergence in 23 (39%) of the evaluable samples. Conclusion: Our real-world data analysis indicates that the possibilities of LB are not yet exploited in everyday clinical practice. Currently, the variety of methods and lack of standardization, as well as restricted reimbursement for liquid based CGP hinder the use of LB in clinical routine. To overcome these issues, prospective clinical trials are needed to provide evidence driving the implementation of LB into the management of CRC patients and to support their implementation into clinical guidelines.

Can routine register data be used to identify vulnerable lung cancer patients of suboptimal care in a German comprehensive cancer centre?

OBJECTIVES: Several patient factors have been described to influence access to optimal cancer care like socioeconomic factors or place of residence. In this study, we investigate whether data routinely collected in a clinical cancer registry can be used to identify populations of lung cancer patients with increased risk of not receiving optimal cancer care. METHODS: We analysed data of 837 lung cancer patients extracted from the clinical cancer registry of a German university hospital. We compared patient populations by two indicators of optimal care, namely implementation of tumour board meeting recommendations as well as the timeliness of care. RESULTS: There was a high rate of implementation of tumour board meeting recommendations of 94.4%. Reasons for non-implementation were mainly a patient's own wish or a worsening of the health situation. Of all patient parameters, only tumour stage was associated with the two optimal care indicators. CONCLUSION: Using routine data from a clinical cancer registry, we were not able to identify patient populations at risk of not getting optimal care and the implementation of guideline-conform care appeared to be very high in this setting. However, limitations were the ambiguity of optimal care indicators and availability of parameters predictive for patients' vulnerability.

Information, communication, and cancer patients' trust in the physician: what challenges do we have to face in an era of precision cancer medicine?

PURPOSE: Despite promising achievements in precision cancer medicine (PCM), participating patients are still faced with manifold uncertainties, especially regarding a potential treatment benefit of molecular diagnostics (MD). Hence, MD poses considerable challenges for patient information and communication. To meet these challenges, healthcare professionals need to gain deeper insight into patients' subjective experiences. Therefore, this qualitative study examined information aspects of MD programs in cancer patients. METHODS: In two German Comprehensive Cancer Centers, 30 cancer patients undergoing MD participated in semi-structured interviews on information transfer and information needs regarding MD. Additionally, patients provided sociodemographic and medical data and indicated their subjective level of information (visual analogue scale, VAS, 0-10). RESULTS: On average patients had high levels of information (mean = 7, median = 8); nevertheless 20% (n = 6) showed an information level below 5 points. Qualitative analysis revealed that patients show limited understanding of the complex background of MD and have uncertainties regarding their personal benefit. Further, patients described unmet information needs. Existential threat in awaiting the results was experienced as burdensome. To withstand the strains of their situation, patients emphasized the importance of trusting their physician. CONCLUSION: The challenges in PCM consist in providing unambiguous information, especially concerning treatment benefit, and providing guidance and support. Therefore, psycho-oncology needs to develop guidelines for adequate patient communication in order to help healthcare providers and cancer patients to handle these challenges in the developing field of PCM.

Conceptual framework for precision cancer medicine in Germany: Consensus statement of the Deutsche Krebshilfe working group 'Molecular Diagnostics and Therapy'.

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force 'Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality.

Cancer patients' expectations when undergoing extensive molecular diagnostics-A qualitative study.

OBJECTIVE: Precision cancer medicine (PCM) aims at identifying tumor-driving molecular characteristics to improve therapy. Despite early successes for some cancers, the approach faces manifold challenges. Patients undergoing extensive molecular diagnostics (MD) may hope for personal benefit, although chances are small. In order to offer suitable support to this group, health-care professionals need to gain insight into patients' experience. Thus, this study sought to explore the expectations of cancer patients undergoing MD of their tumor. METHODS: In two German Comprehensive Cancer Centers, 30 patients with advanced-stage cancer who had exhausted conventional treatment and had consented to extensive, research-oriented MD (whole-genome sequencing n = 24, panel sequencing n = 6) participated in semi-structured interviews. Following thematic content analysis by Kuckartz, the interview transcripts were coded for expectations of MD participation and topics closely related. Moreover, patients completed questionnaires on their sociodemographic characteristics, medical history, and psychosocial distress. RESULTS: Patients reported to be expecting (a) an improvement of their treatment, (b) a contribution to research, and/or (c) additional insight to their own cancer. Further, they described to feel individually appreciated and to have a reason to maintain hope for cure or recovery by participating in MD. CONCLUSIONS: Molecular diagnostics participation led patients to feel treated in a more "personalized" way, allowing them a greater sense of control in their situation of severe illness. Oncologists and psycho-oncologists need to ensure comprehensive information and empathetic support for patients undergoing extensive MD to balance their expectations and actual chances of clinical benefit.

Comparative Analysis of Public Knowledge Bases for Precision Oncology.

PURPOSE: Precision oncology depends on the availability of up-to-date, comprehensive, and accurate information about associations between genetic variants and therapeutic options. Recently, a number of knowledge bases (KBs) have been developed that gather such information on the basis of expert curation of the scientific literature. We performed a quantitative and qualitative comparison of Clinical Interpretations of Variants in Cancer, OncoKB, Cancer Gene Census, Database of Curated Mutations, CGI Biomarkers (the cancer genome interpreter biomarker database), Tumor Alterations Relevant for Genomics-Driven Therapy, and the Precision Medicine Knowledge Base. METHODS: We downloaded each KB and restructured their content to describe variants, genes, drugs, and gene-drug associations in a common format. We normalized gene names to Entrez Gene IDs and drug names to ChEMBL and DrugBank IDs. For the analysis of clinically relevant gene-drug associations, we obtained lists of genes affected by genetic alterations and putative drug therapies for 113 patients with cancer whose cases were presented at the Molecular Tumor Board (MTB) of the Charité Comprehensive Cancer Center. RESULTS: Our analysis revealed that the KBs are largely overlapping but also that each source harbors a notable amount of unique information. Although some KBs cover more genes, others contain more data about gene-drug associations. Retrospective comparisons with findings of the Charitè MTB at the gene level showed that use of multiple KBs may considerably improve retrieval results. The relative importance of a KB in terms of cancer genes was assessed in more detail by logistic regression, which revealed that all but one source had a notable impact on result quality. We confirmed these findings using a second data set obtained from an independent MTB. CONCLUSION: To date, none of the existing publicly available KBs on gene-drug associations in precision oncology fully subsumes the others, but all of them exhibit specific strengths and weaknesses. Consideration of multiple KBs, therefore, is essential to obtain comprehensive results.

[Interdisciplinary Recommendations for the Treatment of Metastatic Renal Cell Carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms .

Thanks to the use of targeted therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved significantly. A median overall survival of more than 2 years is a realistic claim. These improvements are also reflected in recent discussions about 3 and more lines of therapy.Sunitinib, pazopanib, the combination of bevacizumab and interferon alpha, and temsirolimus are approved for first-line therapy of mRCC. Sunitinib and pazopanib are also approved for second-line therapy, which, for pazopanib, is confined to the use after cytokine failure. Everolimus (after tyrosine kinase inhibitor (TKI) treatment), sorafenib (after cytokines) and axitinib (after treatment with sunitinib or cytokines) are other compounds available for second-line therapy.3 new substances have recently been approved for second-line therapy: Nivolumab, cabozantinib, and lenvatinib combined with everolimus can be used after VEGF-targeted treatment has failed. It is for the first time that targeted immunotherapy and a combination of targeted substances are available for the treatment of mRCC.There is no new insight as to an optimal sequence therapy. Study results from a phase III trial suggest that the sequences sorafenib-sunitinib and sunitinib-sorafenib are equally effective.The purpose of an interdisciplinary expert meeting on RCC was to work out joint treatment recommendations based on current data and clinical experience and to integrate them into clinical routine practice. The results are presented in this publication.

The Interdisciplinary Management of Brain Metastases.

BACKGROUND: 20-40% of patients with malignant tumors have one or more brain metastases in the course of their illness. Brain metastases are the first manifestation of cancer in 5-10%. Manifestations such as intracranial hypertension or focal neurologic deficits are seen in over 80% of patients with brain metastases. Uncertainty surrounds the treatment of patients with intracranial metastases, as the existing data are derived from trials with low levels of evidence. METHODS: This article is based on a selective literature review and on the authors' own experience of 100 consecutive patients who underwent surgery at the Department of Neurosurgery at Ruhr University Bochum (RUB), Germany. RESULTS: Multimodal treatment enables successful surgery for an increasing number of patients with brain metastases. The modalities and goals of treatment are established for each patient individually by an interdisciplinary tumor board. Drug therapy is usually indicated. Surgical resection followed by stereotactic radiotherapy prolongs mean survival by 3-6 months and lowers the risk of recurrence from 40% to 12.5%. In the authors' own experience, even seriously ill patients can benefit from the resection of brain metastases. The 30-day morbidity was 29%, accounted for mainly by medical complications such as pulmonary embolism, renal failure, and sepsis. CONCLUSION: Through the close interdisciplinary collaboration of neurosurgeons, radiation oncologists, and medical oncologists, the symptomatic state and the prognosis of patients with brain metastases can be improved. Longer overall survival implies that further studies will have to pay special attention to the toxicity of treatment.

Regional hyperthermia combined with chemotherapy in paediatric, adolescent and young adult patients: current and future perspectives.

Here we evaluate the current status of clinical research on regional hyperthermia (RHT) in combination with chemotherapy or radiation therapy in paediatric oncology.Data were identified in searches of MEDLINE, Current Contents, PubMed, and references from relevant articles using medical subject headings including hyperthermia, cancer, paediatric oncology, children, radiation therapy and chemotherapy. Currently, only two RHT centres exist in Europe which treat children. Clinical RHT research in paediatric oncology has as yet been limited to children with sarcomas and germ cell tumours that respond poorly to or recur after chemotherapy. RHT is a safe and effective treatment delivering local thermic effects, which may also stimulate immunological processes via heat-shock protein reactions. RHT is used chiefly in children and adolescents with sarcomas or germ cell tumours located in the abdomino-pelvic region, chest wall or extremities to improve operability or render the tumour operable. It could potentially be combined with radiation therapy in a post-operative R1 setting where more radical surgery is not possible or combined with chemotherapy instead of radiation therapy in cases where the necessary radiation dose is impossible to achieve or would have mutilating consequences. RHT might also be an option for chemotherapy intensification in the neoadjuvant first-line treatment setting for children and adolescents, as was recently reflected in the promising long-term outcome data in adults with high-risk soft tissue sarcomas (EORTC 62961/ESHO trial).The limited data available indicate that combining RHT with chemotherapy is a promising option to treat germ cell tumours and, potentially, sarcomas. RHT may also be beneficial in first-line therapy in children, adolescents and young adults. The research should focus on optimising necessary technical demands and then initiate several clinical trials incorporating RHT into interdisciplinary treatment of children, adolescents and young adults that include translational research components exploring potential immunological mechanisms of action.

Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors.

PURPOSE: Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy. METHODS: Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed. RESULTS: Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1-10.4) and 18.0 months (12.6-23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13). CONCLUSIONS: Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.

Systemic immune tuning in renal cell carcinoma: favorable prognostic impact of TGF-ß1 mRNA expression in peripheral blood mononuclear cells.

Renal cell carcinoma (RCC) can inhibit protective immunity by induction of immunosuppressive cells that produce inhibitory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-ß. If this immunosuppression influences response to kinase inhibitors such as sorafenib is not known. Therefore, we asked for the prognostic influence of cells with immunosuppressive properties in peripheral blood (pB) in a cohort of metastatic clear cell renal cell carcinoma (mRCC) patients uniformly receiving sorafenib treatment. IL-10 and TGF-ß mRNA levels, regulatory T-cell (Treg) counts, and frequencies of IL-10/TGF-ß producing mononuclear cell subsets were determined in pB from 46 patients with mRCC before receiving sorafenib treatment. Relationship between established clinical and laboratory prognostic factors and outcome were examined by univariate and multivariate Cox regression analysis. IL-10 and TGF-ß1 mRNA levels, and frequencies of CD4(+)CD25high/CD3(+) and CD4(+)CD25highFoxP3(+)/CD3(+)Treg cells were significantly higher in mRCC patients compared with healthy individuals. Monocytes were suggested as main producers of IL-10 and TGF-ß. In a multivariate analysis low ECOG score and-surprisingly-high TGF-ß1 mRNA levels were independently associated with favorable progression-free survival (P=0.005 and P=0.003, respectively) and overall survival (P=0.001 and P=0.039, respectively). In conclusion, mRCC is associated with an immunosuppressive phenotype in peripheral blood. The positive prognostic influence of high TGF-ß1 mRNA expression levels may reflect immune promoting functions of TGF-ß in combined activity with inflammatory cytokines.

Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib.

BACKGROUND: Sorafenib and sunitinib are tyrosine kinase inhibitors with largely overlapping specificities, approved for the treatment of metastatic renal-cell carcinoma (RCC). It was unclear whether the similarities of the two drugs would lead to complete cross-resistance, or whether sequential application would be efficacious. METHODS: Patients with metastatic RCC and progression on sorafenib treatment were treated with repeated cycles of sunitinib, 50 mg for 4 weeks, followed by a 2-week break. Response (Response Evaluation Criteria in Solid Tumors, RECIST) was assessed every second cycle. RESULTS: A total of 22 patients with progression on sorafenib were accrued. Initially, sorafenib treatment was efficacious in all patients, with 7 showing partial response (PR) and 15 stable disease (SD), and subsequent disease progression. With 4 PRs (18%) and 12 SD (55%) a disease control rate of 73% was achieved. The median progression-free survival (PFS) on sunitinib was 21.5 weeks; median overall survival (OS) was not reached. Estimated 1-year PFS and OS were 31 and 60%, respectively. There was no apparent relationship between response to sorafenib and outcome on sunitinib. CONCLUSION: In our cohort of patients with RCC and progression after initial efficacy of sorafenib, the efficacy data of second-line sunitinib were close to published results of first-line treatment, suggesting limited clinically relevant cross-resistance.