Ethical challenges of precision cancer medicine.

Amongst common diseases, cancer is often both a leader in self-regulatory policy, or the field for contentious ethical issues such as the patenting of the BRCA1/2 genes. With the advent of genomic sequencing technologies, achieving precision cancer medicine requires prospective norms due to the large and varied sources of data involved. Here, we discuss the ethical and legal aspects of the policy debate around the relevant topics in precision cancer medicine: the return of incidental findings and sequencing raw data to patients, the communication of genetic results to patients' relatives, privacy and communication risks with concomitant oversight strategies, patient participation and consent models. We present the arguments and empirical data supporting specific policy solutions delineating still contested areas. What type of consent and oversight are required to acquire genomic data or to access it where desired, either by the participant/patient or third-party researchers? Most of the raw sequencing data is still uninterpretable and the variants revealed subject to reinterpretation over time. No doubt the ethical challenges of precision cancer medicine are a prototype of what's to come for other diseases. They are also paradigmatic for regulatory and ethical questions of the translational endeavors since the two worlds - basic science and patient care - are governed by different ethical and legal principles that need to be reconciled in precision cancer medicine.

Dealing with Family Conflicts in Decision-making in End-of-Life Care of Advanced Cancer Patients.

PURPOSE OF REVIEW: The family plays a significant role in end-of-life care and decision-making with advanced cancer patients. This non-systematic review aims to summarize the family role and possible emerging conflicts and problems related to family involvement in decisions with advanced cancer patients. RECENT FINDINGS: Four important domains were identified: (1) discordance between patients and caregivers' understanding of prognosis and goals of care; (2) internal family conflicts; (3) cultural differences regarding the role of the family in end-of life decision-making; (4) the burden on caregivers through caring for cancer patients. Based on the findings, we formulated some implications to consider for clinical practice. We suggest to involve the family in decision-making, to ascertain patients' wish for family involvement and if necessary, taking a mediator role between patients and their caregivers; to be aware of "invisible" family influence on patients' decisions; to assess systematically family burden and needs; to provide timely information, psychological support interventions and palliative care.

Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3).

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months; p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.

Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate.

BACKGROUND: Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited. METHODS: Retrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017. RESULTS: Of 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years. CONCLUSIONS: EP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.

[Frequency and Timing of Decisions to Limit Intensive Medical Care and Tumor-Specific Therapy in University Hematology and Oncology]. / Häufigkeit und Zeitpunkt von Entscheidungen gegen intensivmedizinische Maßnahmen und tumorspezifische Therapien in einer universitären Hämatologie und Onkologie.

Background Decisions to limit treatment (DLT) are important in order to prevent overtreatment at the end of life. However, they are not always discussed with the patient in advance or sufficiently documented. In a study to improve DLT in patients with an advanced hematological/ oncological disease we examined how often DLT precede deaths and how early they are determined. Methods In a period of 6 months, 567 patients with advanced hematological/ oncological neoplasias had been recruited for the cross-sectional study at the University hospital in Munich. Using a standardized registration form an embedded researcher documented which DLT were determined for the patients and which of them were implemented until death. Results For 26 % (n = 147) of the 567 patients a DLT was determined. These DLT were mostly documented in writing from the beginning on (90 %; n = 132), 20 % (n = 30) were modified. The proportion of deceased patients with DLT was 82 % (n = 62 of 76 deceased). The median time between the initial determination of a DLT and the patient's death was 6 days at normal ward and 10.5 days at palliative ward. Compared to hematological patients, DLT were more frequently diagnosed in patients with an oncological disease (64 vs. 36 %) and the decisions were made slightly earlier (7 vs. 5 days before death). Conclusion Our results show that DLT precede the death of many patients with a hematological/ oncological disease, but usually are made in the last week of life. This leads to the risk that the remaining few days to death are not sufficient for discussions with all parties involved and the planning of the end of life. These findings resulted in the development of an ethics policy for treatment limitation in cancer patients, which should support the concept of advance care planning. The project is funded by the German Cancer Aid.

Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma.

Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy are limited. Topotecan is an approved second-line chemotherapy for small cell lung cancer (SCLC). NEC is often considered to show a biological behavior similar to SCLC. The aim of this study was to analyze the efficacy of topotecan in pretreated metastatic NEC patients. We performed a retrospective analysis of all patients treated with topotecan for metastatic NEC who presented at our center between January 2005 and December 2014 (n = 30). All 30 patients had received at least a platinum and etoposide containing regimen as prior chemotherapy. Median proliferation rate (Ki67) was 80%. As best response to topotecan five patients showed a stable disease, two patients a partial remission, resulting in a disease control rate of 23%. Of the remaining 23 patients, 14 (47%) showed a progressive disease, nine (30%) died before radiologic response could be evaluated. Median progression-free (PFS) and overall survival (OS) after start of topotecan was 2.1 and 4.1 months, respectively. In the subgroup analysis, patients with unknown primary (vs. those with a known primary) showed a significantly prolonged PFS of 3.5 months (vs. 1.9, P = 0.0107) and OS of 6.7 months (vs. 2.6 months, P = 0.0168). Grade 3/4 hematotoxicity was observed in 60% of patients. Topotecan shows only moderate antitumor activity in metastatic NEC. Disease control rate is lower than reported for SCLC. However, antitumor activity of topotecan seems higher in patients with unknown primary.