Jitka Abrahámová

Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study

BACKGROUND A retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed. PATIENTS AND METHODS Data on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand-foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash. RESULTS The cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort. CONCLUSION The presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.

Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma-data from the Czech registry

BACKGROUND Sequential therapy with tyrosine kinase inhibitors (TKIs), sunitinib and sorafenib, is a common treatment choice for patients with advanced/metastatic renal cell carcinoma (mRCC) despite lack of randomised trials. The aim of this retrospective registry-based study was to analyse the outcomes of RCC patients treated with sunitinib-sorafenib or sorafenib-sunitinib sequence. PATIENTS AND METHODS The Czech database containing information on patients treated for mRCC using targeted agents was used as a source of data for retrospective analysis. There were 138 patients treated with sunitinib-sorafenib sequence and 122 patients treated with sorafenib-sunitinib sequence. RESULTS Progression-free survival (PFS) was 17.7 months for patients treated with sunitinib-sorafenib sequence and 18.8 months for those receiving sorafenib followed by sunitinib (P = 0.47). Overall survival (OS) at 1 year was 83% [95% confidence interval (CI) 77% to 90%] for patients treated with sunitinib-sorafenib and 84% (95% CI 77% to 91%) for sorafenib-sunitinib patients (P = 0.99). Treatment toxic effects were predictable but a significant proportion of patients (up to 14%-25% for different lines of therapy and used TKI) switched between TKIs or discontinued TKI therapy because of toxicity. CONCLUSIONS In contrast to most of the previously published reports, we have not observed improved PFS or OS for mRCC patients treated with the sorafenib-sunitinib sequence as compared to the sunitinib-sorafenib sequence.

Molecular biology of testicular germ cell tumors: Unique features awaiting clinical application

Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men characterized by distinct biologic features and clinical behavior. Both genetic predispositions and environmental factors probably play a substantial role in their etiology. TGTCs arise from a malignant transformation of primordial germ cells in a process that starts prenatally, is often associated with a certain degree of gonadal dysgenesis, and involves the acquirement of several specific aberrations, including activation of SCF-CKIT, amplification of 12p with up-regulation of stem cell genes, and subsequent genetic and epigenetic alterations. Their embryonic and germ origin determines the unique sensitivity of TGCTs to platinum-based chemotherapy. Contrary to the vast majority of other malignancies, no molecular prognostic/predictive factors nor targeted therapy is available for patients with these tumors. This review summarizes the principal molecular characteristics of TGCTs that could represent a potential basis for development of novel diagnostic and treatment approaches.

Detection of second malignancies during long-term follow-up of testicular cancer survivors.

Second cancers are an important cause of mortality and morbidity in long‐term survivors of testicular germ cell tumors (TGCTs). Studies on the impact of follow‐up for the first tumor on the outcome of second malignancies are lacking. The aim of this study was to study the details of diagnosis of second cancers and the role of focused oncology follow‐up.

Trends in stage-specific population-based survival of cancer patients in the Czech Republic in the period 2000-2008

BACKGROUND The objective of this study was to assess trends in overall and in stage-specific 5-year relative survival rates of the Czech cancer patients between periods 2000-2004 and 2005-2008. METHODS All Czech cancer patients diagnosed between 1995 and 2008 were included in the analysis. Period analysis was employed to calculate 5-year relative survival for 21 cancers. RESULTS Significant improvements in crude 5-year relative survival for 14 of 21 assessed types of cancer, including the most frequent diagnoses, such as, colorectal, prostate, breast, lung, kidney, pancreatic, and bladder cancer and melanoma, were identified. Moreover, in case of colorectal, lung, and prostate cancer, improvement in stage-specific 5-year relative survival was confirmed as statistically significant for all clinical stages. No diagnosis showed significant decrease in the 5-year relative survival. However, the 5-year relative survival remained poor in patients with metastatic cancers at diagnosis, particularly in case of liver, pancreatic, lung, and oesophageal cancer. CONCLUSIONS The cancer-specific outcomes in the Czech Republic are improving. Nevertheless, despite the overall significant improvement in 5-year relative survival of most of the cancer diagnoses, the high proportion of patients primarily diagnosed with metastatic cancer still represents a substantial challenge for prevention and early detection.

Current standards in the treatment of metastatic breast cancer with focus on Lapatinib: a review by a Central European Consensus Panel

ZusammenfassungSowohl Früherkennung als auch die Entwicklung neuer therapeutischer Optionen haben dazu geführt, dass bei Frauen mit Brustkrebs seltener ein metastasiertes Mammakarzinom diagnostiziert wird. Dennoch entwickelt etwa ein Drittel der Patienten, bei denen ein Mammakarzinom im frühen Stadium diagnostiziert wurde, irgendwann metastasierten Brustkrebs. Dazu kommt, dass ungefähr 25–30 % der Patienten mit Brustkrebs eine Überexpression des Wachstumsfaktors HER-2 aufweisen, der mit einem aggressiven Tumor-Phänotyp und schlechter Prognose assoziiert ist. Allerdings hat die Identifikation des HER-2-Proteins zur Entwicklung hoch effektiver Therapeutika geführt, die sich gegen diesen Rezeptor richten. Trastuzumab, ein rekombinanter, humanisierter, monoklonaler Antikörper, der an die extrazelluläre Domäne des HER-2-Proteins bindet, zeigte einen signifikanten Vorteil bei metastasiertem Brustkrebs und im frühen Stadium. Da es bei einigen Frauen nach adjuvanter Therapie zu einem Rezidiv kommt, und metastasierter Brustkrebs im Verlauf einer Trastuzumab-Therapie Resistenzen entwickeln kann, besteht Bedarf an alternativen Behandlungsoptionen, um die HER-2-Signalübertragung zu blockieren. Eine dieser Therapiemöglichkeiten ist Lapatinib, ein oral aktives kleines Molekül, das die Tyrosinkinase von HER-2 und den epidermalen Wachstumsfaktor-Rezeptor Typ 1 (EGFR) inhibiert. In diesem Konsensus-Statement werden die derzeitigen Behandlungsoptionen des metastasierten und lokal fortgeschrittenen Mammakarzinoms mit speziellem Fokus auf Lapatinib diskutiert.SummaryIn breast cancer, early detection as well as new developments in therapeutic options has resulted in less patients presenting with metastatic disease. However, about one-third of women with early stage breast cancer will eventually develop metastatic disease. Furthermore, approximately 20–30% of patients with breast cancer have tumors that overexpress human epidermal growth factor receptor (HER-2), which is associated with an aggressive tumor phenotype and poor prognosis. The identification of the HER-2 protein led to the development of highly effective therapeutics directed at this receptor. Trastuzumab, a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER-2 protein, has shown significant clinical benefit in metastatic and early-stage HER-2-positive breast cancer. Since the cancer recurs after adjuvant therapy in some women, and metastatic breast cancer eventually develops resistance to trastuzumab, there is a need for alternative treatment modalities to block HER-2 signaling. One of these treatment options is lapatinib, an orally active small molecule that inhibits the tyrosine kinases of HER-2 and the epidermal growth factor receptor type 1 (EGFR). In this consensus statement current treatment options in metastatic and locally advanced disease are discussed with a special focus on lapatinib.

Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors

PURPOSE Wilms tumor gene 1 (WT1), a zinc-finger transcription factor essential for testis development and function, along with other genes, was investigated for their role in the pathogenesis of testicular germ cell tumors (TGCT). METHODS In total, 284 TGCT and 100 control samples were investigated, including qPCR for WT1 expression and BRAF mutation, p53 immunohistochemistry detection, and massively parallel amplicon sequencing. RESULTS WT1 was significantly (p < 0.0001) under-expressed in TGCT, with an increased ratio of exon 5-lacking isoforms, reaching low levels in chemo-naïve relapsed TGCT patients vs. high levels in chemotherapy-pretreated relapsed patients. BRAF V600E mutation was identified in 1% of patients only. p53 protein was lowly expressed in TGCT metastases compared to the matched primary tumors. Of 9 selected TGCT-linked genes, RAS/BRAF and WT1 mutations were frequent while significant TP53 and KIT variants were not detected (p = 0.0003). CONCLUSIONS WT1 has been identified as a novel factor involved in TGCT pathogenesis, with a potential prognostic impact. Distinct biologic nature of the two types of relapses occurring in TGCT has been demonstrated. Differential mutation rate of the key TGCT-related genes has been documented.

Locally advanced breast cancer in elderly patients

BACKGROUND Although locally advanced breast cancer (LABC) is more common in the elderly population, there is little data on the clinical characteristics and survival of these patients. The aim of the present study was to compare different factors affecting survival in elderly patients with LABC. METHODS Retrospective analysis was carried out on a cohort of 80 patients aged 70 to 96 years, diagnosed with LABC defined as T3 N1, T4 N0, any N2 or N3, and M0. The prognostic impact of selected clinical parameters including age, comorbidities, tumour grade, HER2 status, tumour stage, local therapies, and systemic treatments was studied. RESULTS The median age of the patients was 79 years. The majority (n=53; 66%) had at least one significant comorbidity according to the Charlson score evaluation. The median overall survival was 50.6 months. As expected, hormonal therapy was the dominant mode of systemic treatment, but 24% also received at least one line of chemotherapy. Local therapies including surgery and/or radiotherapy were applied in 58% of patients. CONCLUSIONS The diagnosis of LABC in the elderly is associated with poor prognosis. Age and serious comorbidities were negative prognostic factors.

Clinical outcomes of patients with nonseminomatous germ cell tumours and negative postchemotherapy positron emission tomography.

Univariate and multivariate analyses were carried out to identify factors associated with the failure of 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to correctly predict relapse-free survival in patients with nonseminomatous germ cell tumours. Ninety-three patients with negative postchemotherapy FDG-PET scan were analyzed in the retrospective study. The FDG-PET result was validated by long-term follow-up and, in some patients, by resection of the residual tumour mass. The negative predictive value of FDG-PET was 81.7%. Higher tumour marker levels and nodal stage at diagnosis, presence of residual mass, and teratoma or teratocarcinoma in the primary histology were associated with FDG-PET failure.

[Cost analysis of radiotherapy provided in inpatient setting - testing potential predictors for a new prospective payment system].

BACKGROUND As a part of the development of a new prospective payment model for radiotherapy we analyzed data on costs of care provided by three comprehensive cancer centers in the Czech Republic. Our aim was to find a combination of variables (predictors) which could be used to sort hospitalization cases into groups according to their costs, with each group having the same reimbursement rate. We tested four variables as possible predictors -  number of fractions, stage of disease, radiotherapy technique and diagnostic group. METHODS We analyzed 7,440 hospitalization cases treated in three comprehensive cancer centers from 2007 to 2011. We acquired data from the I COP database developed by Institute of Biostatistics and Analyses of Masaryk University in cooperation with oncology centers that contains records from the National Oncological Registry along with data supplied by healthcare providers to insurance companies for the purpose of retrospective reimbursement. RESULTS When comparing the four variables mentioned above we found that number of fractions and radiotherapy technique were much stronger predictors than the other two variables. Stage of disease did not prove to be a relevant indicator of cost distinction. There were significant differences in costs among diagnostic groups but these were mostly driven by the technique of radiotherapy and the number of fractions. Within the diagnostic groups, the distribution of costs was too heterogeneous for the purpose of the new payment model. CONCLUSION The combination of number of fractions and radiotherapy technique appears to be the most appropriate cost predictors to be involved in the prospective payment model proposal. Further analysis is planned to test the predictive value of intention of radiotherapy in order to determine differences in costs between palliative and curative treatment.