Indications for venous access in oncology - recommendations of national professional societies and current state in the Czech Republic.

BACKGROUND: The aim of the paper is to present the current recommendations and indications of venous access in oncology which reflect and recognize the opinions of national and international professional societies. It focuses exclusively on the indications of intravenous catheter placement for anticancer treatment, such as medium-term and long-term venous accesses. MATERIALS AND METHODS: The survey results obtained from a national questionnaire of 24 oncology centers identified the current situation in the Czech Republic. There were evaluated relevant data on the number of and the criteria for the introduction of venous accesses provided by physicians. Comparisons were made between current oncological practice and recommendations provided by evidence-based medicine. RESULTS: At each center surveyed in the Czech Republic, an average of 130 ports and 80 permanent implanted central catheters are introduced annually. The ports are increasingly indicated, with over a half of the centers surveyed introducing ports to more than 100 patients a year, with four centers introducing a total of 1,600 ports annually. In all centers, the decision for venous access is made by an oncologist. However, most procedures are performed by a doctor of another specialization, most often by a surgeon, a radiologist or an anesthesiologist. More than a half of the indications for venous access placement result from poor peripheral venous system or complications of parenteral therapy, not from comprehensive assessment prior to the initiation of the therapy. CONCLUSION: Based on our findings, we developed general indications and recommendations for venous access to cancer patients which represent the consensus of an interdisciplinary team of specialists, predominantly from the committee of professional societies - the Society for Ports and Permanent Catheters, the Working Group of Nutritional Care in Oncology of the Czech Oncological Society and the Society of Clinical Nutrition and Intensive Metabolic Care. The number of introduced venous access catheters remains insufficient to meet the needs in the Czech Republic, which necessitates increased awareness and possibilities for safe drug administration.

Regorafenib for Metastatic Colorectal Cancer: An Analysis of a Registry-Based Cohort of 555 Patients.

PURPOSE: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry. METHODS: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified. RESULTS: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0-23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2-3.7 months) and 9.3 months (95% CI 8.3-10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4-72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS. CONCLUSION: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.

Gastric tumors in children: single-center study with emphasis on treatment of repeated recurrence.

PURPOSE: Analysis of surgical management and survival of pediatric patients with gastric tumors treated at our institution. METHODS: A retrospective study of patients with primary gastric tumors treated between 1993 and 2018 was conducted. RESULTS: Eight patients, five girls and three boys, were diagnosed with gastric tumors at an average age of 10.4 years (1 day-15.4 years). Surgical management included Billroth type I procedure in five and tumor excision in three patients. Histology revealed gastrointestinal stromal tumor (GIST) in four patients and one of each of schwannoma, myofibroblastic tumor, hamartoma and teratoma. Microscopically clear margins were reported in six patients. Repeated local recurrence occurred in three patients (2 × GIST, 1 × myofibroblastic tumors) who consequently underwent three, four and six reoperations. One of these patients had liver metastases, which were managed with ligation of the hepatic arteries. This patient was also diagnosed with a lung hamartoma, which was treated with a lobectomy. Survival rate was 100% with a median follow-up of 8.6 years (7 months-25.5 years). CONCLUSIONS: Gastric tumors are rare in children and represent a management challenge. Repeated recurrence of GISTs and myofibroblastic tumors remains frequent even after complete resection and may necessitate multiple surgeries, therefore patients require a lifelong follow-up.

Safety and Effectiveness of Aflibercept + Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) for the Treatment of Patients with Metastatic Colorectal Cancer (mCRC) in Current Clinical Practice: OZONE Study.

For patients with metastatic colorectal cancer (mCRC) that have failed a first-line oxaliplatin-based regimen, the preferred treatment option is an irinotecan-based regimen. This prospective, observational, noncomparative, post-authorization safety study (OZONE) evaluated the safety and effectiveness of aflibercept plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients with mCRC treated in daily practice after failure of an oxaliplatin-based regimen. Patients were grouped by age, renal impairment, hepatic impairment, race, number, and type of prior anticancer therapy. Of 766 treated patients enrolled, 59.5% were male, 94.8% had an Eastern Cooperative Oncology Group performance status of 0-1, all received previous chemotherapy (97.8% including oxaliplatin), and 58.6% had prior exposure to bevacizumab. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 68.3% of patients. Neutropenia, hypertension, diarrhea, and asthenia were the most frequently occurring grade ≥ 3 TEAEs. Antivascular endothelial growth factor class events were infrequent. Subgroup analyses did not reveal major differences in the safety profile according to age, renal and hepatic status, race, or prior anticancer therapy. For the total population, median overall survival was 12.5 months, median progression-free survival was 6.1 months, and overall response rate was 16.3%. Aflibercept in combination with FOLFIRI is a safe and efficacious regimen administered in current clinical practice to patients with mCRC previously treated with oxaliplatin. The study results, conducted in real-world clinical practice with a less selected patient population, are aligned with the VELOUR (NCT00561470) trial and no new safety issues were identified.

Gastrointestinal stromal tumors - Summary of mutational status of the primary/secondary KIT/PDGFRA mutations, BRAF mutations and SDH defects.

The most important findings revealing pathogenesis, molecular characteristics, genotyping and targeted therapy of gastrointestinal stromal tumors (GISTs) are activated oncogenic mutations in KIT and PDGFRA genes. Imatinib mesylate (IM), which inhibits both KIT and PDGFRA receptors, significantly improved treatment of advanced (metastatic, recurrent, and/or inoperable) GISTs. However, in a significant number of patients the treatment fails due to the primary or secondary resistance to targeted therapy. Most common cause of secondary resistance is a presence of secondary mutations. Approximately 15% of adult patients with GISTs are negative for mutations in KIT or PDGFRA genes. These so-called wild-type GISTs appear to be characterized by other oncogenetic drivers, including mutations in BRAF, RAS, NF1 genes, and subunits of succinate dehydrogenase (SDH) complex. In the present study we investigated 261 tumour specimens from 239 patients with GIST. Primary mutations were detected in 82 % tumor specimens. 66 of them were in KIT, and 16 % in PDGFRA genes. Remaining 18 % were KIT/PDGFRA wild-type. Secondary KIT mutations were detected in 10 from 133 (7 %) patients treated with IM. We examined secondary KIT mutations in exons 13 and 17 and secondary PDGFRA mutation in exon 18 in sixteen progressive tumors and/or metastasis (from overall 22 samples). We identified BRAF V600E point mutation in 4 % of KIT/PDGFRA wild-type GIST patients. Moreover, we analysed SDH complex mutations in 4 younger patients (15, 33, 37, and 45 years old) from 44 patients without KIT, PDGFRA, and BRAF mutations. Two patients (a 37-year old man, and a 33-year old woman) had defects of the SDH complex. Our findings of mutational status of the primary and secondary KIT/PDGFRA mutations in patients with GIST confirm mechanisms of primary and secondary resistance, and also intralesional and interlesional heterogeneity of secondary mutations within and between progressive lesions. Moreover, detection of V600E BRAF mutation and defects of SDH complex in KIT/PDGFRA wild-type GISTs confirm their activation and allow for a selection of targeted therapy.

Regorafenib in the Real-Life Clinical Practice: Data from the Czech Registry.

OBJECTIVE: To describe the use of regorafenib for the treatment of metastatic colorectal cancer (mCRC) in clinical practice in the Czech Republic, and to describe the clinical outcomes of patients in terms of safety and survival. PATIENTS AND METHODS: The data of patients treated with regorafenib were extracted from the national CORECT registry. The CORECT registry is a non-interventional post-marketing database, gathering information about patients with CRC and treated with targeted agents. Twenty oncology centres in the Czech Republic contributed to this registry. Collected data included patients' characteristics, disease history, cancer treatments, response to treatments and safety. RESULTS: A total of 148 patients treated with regorafenib in clinical practice were analysed. At regorafenib initiation, almost all patients were fully active or slightly restricted in physical activity. Regorafenib was not administered as first-line treatment in any patient. Median progression-free survival was 3.5 months and median overall survival was 9.3 months. One-year survival rate was 44.6 %. Four partial responses were observed and 51 stable diseases. Progression was observed in 66 patients (44.6 %). The main reported adverse events were skin toxicity (5.4 %) and fatigue (2.0 %). CONCLUSIONS: Regorafenib is a well-established treatment for pretreated patients with mCRC, however real-life data are scarce. Our results demonstrated slightly better efficacy of regorafenib and better safety profile in patients with mCRC compared to the randomised trials.

Bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer: Czech registry data.

AIM: This retrospective analysis investigated the effectiveness of combination therapy with bevacizumab and chemotherapy in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer. PATIENTS & METHODS: Patients with KRAS wild-type metastatic colorectal cancer in the CORECT registry who initiated treatment with bevacizumab between 2008 and 2012 were enrolled. Overall survival and progression-free survival were the main effectiveness end points. RESULTS: A total of 981 patients were enrolled. Median progression-free survival was 11.3 months (95% CI: 10.7-11.8) and median overall survival was 28.4 months (95% CI: 26.2-30.6). The most common adverse events were thromboembolic disease (4%) and hypertension (3.5%). CONCLUSION: This retrospective analysis shows the effectiveness of bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer.

Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts.

BACKGROUND: The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation. METHODS: Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST. FINDINGS: Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90). INTERPRETATION: The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes. FUNDING: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.

FOCUS on FOCIS: combined chemo-immunotherapy for the treatment of hormone-refractory metastatic prostate cancer.

Immunotherapy has emerged as another treatment modality in cancer. The goal of immunotherapy in advanced cancer patients does not have to be the complete eradication of tumor cells but rather the restoration of a dynamic balance between tumor cells and the immune response. Appropriate combination of tumor mass reduction (by surgery and/or chemotherapy) and neutralization of tumor-induced immunosuppression might set the right conditions for the induction of anti-tumor immune response by active immunotherapy. We review experimental basis and key concepts of combined chemo-immunotherapy and document its principles in the case report of patient with hormone refractory metastatic prostate cancer with sinister prognosis. More than four hundred prostate cancer patients have been treated with DC-based immunotherapy and tumor-specific immune responses have been reported in two-thirds of them. In half of these patients, DC immunotherapy resulted in transient clinical responses. Tregs, among other factors, potently inhibit tumor-specific T cells. Prostate cancer patients have elevated numbers of circulating and tumor infiltrating Tregs and there is evidence that Tregs increase tumor growth in vivo. Because of the high frequency of circulating Tregs in our patients, we first administered metronomic cyclophosphamide. After obtaining IRB approval, we started regular vaccinations with dendritic cells (DCs) loaded with killed prostate cancer cells. In accordance with the principles of combined immunotherapy, we continued palliative chemotherapy with docetaxel to reduce the tumor cell burden. DC-based vaccination induced prostate cancer cell-specific immune response. Combined chemo-immunotherapy consisting of alternate courses of chemotherapy and vaccination with mature DCs pulsed with LNCap prostate cancer cell line led to the marked improvement in the clinical and laboratory presentation and to the decrease of PSA levels by more than 90%.