A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients.

Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS). Methods: A new parameter, called "individual drug score" (IDS) was calculated by summing the "drug score"-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS. Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p <0.001). In multivariate analysis IDS proved to be an independent marker of TD and OS. The same analysis was performed in a separate group of 81 patients receiving AA+dexamethasone treatment. The previously observed relationships were observed again between IDS and TD or OS. After combining the AA+prednisolone and AA+dexamethasone groups, analysis of the IDS composition showed that patients in the high IDS group not only used more drugs (p <0.001), but their drugs also had a higher mean DS (p = 0.001). Conclusion: The more co-drugs with high DS, the longer the duration of AA treatment and OS, emphasizing the need for careful co-medication planning in patients with mCRPC treated with AA. It is recommended that, where possible, co-medication should be modified to minimize the number of drugs with negative DS and increase the number of drugs with high DS. Our new model can presumably be adapted to other drugs and other cancer types (or other diseases).

[Fertility preservation in testicular cancer patients]. / Heretumoros betegek termékenyítoképességének vizsgálata.

Germ cell tumors of the testicle account for 1% of all tumors. Testicular cancer (TC) is the most common malignancy in men aged 15-35 years. Patients with TC have an excellent survival rate but often have not yet attempted to father children, and fertility is one of the main concerns of survivors, therefore it is important to preserve it. The most commonly used method is sperm banking. Retrospective analysis of the Hungarian data showed that in case of testicular cancer spermatogenesis is more impaired in the more advanced disease. No correlation was found among the histological types and the proportion of azoo- and oligozoospermia. The parameters of testicular cancer and non-Hodgkin lymphoma patients were worse compared to the normal population. Sperm cryopreservation prior to initiating life-saving cancer treatment offers men the best chance to father children and should be offered to all men with testicular cancer before chemotherapy, since cytostatic therapy may lead to infertility.

Predictive Markers of First Line Pazopanib Treatment in Kidney Cancer.

Real-world evidence from clinical practices is fundamental for understanding the efficacy and tolerability of medicinal products. Patients with renal cell cancer were studied to gain data not represented by analyses conducted on highly selected patients participating in clinical trials. Our goal was to retrospectively collect data from patients with advanced renal tumours treated with pazopanib (PZ) to investigate the efficacy, frequency of side effects, and searching for predictive markers. Eighty-one patients who had received PZ therapy as first-line treatment were retrospectively evaluated. Overall survival (OS), progression-free survival (PFS) were assessed as endpoints. Median PFS and OS were 11.8 months (95% CI: 8.8-22.4); and 30.2 months (95% CI: 20.3-41.7) respectively. Severe side effects were only encountered in 11 (14%) patients. The presence of liver metastasis shortened the median PFS (5.5 vs. 14.8 months, p = 0.003). Median PFS for patients with or without side effects was 25.6 vs. 7.3 months, respectively (p = 0.0001). Patients younger than 65 years had a median OS of 41.7 months vs. 25.2 months for those over 65 years of age (p = 0.008). According to our results absence of liver metastases, younger age (<65 years) and presence of side effects proved to be independent predictive markers of better PFS and OS.

Sunitinib Rechallenge After Other Targeted Therapies in Metastatic Renal Cell Carcinoma Patients: A Single-Center, Retrospective Study.

BACKGROUND: Sunitinib is still one of the standard therapies in metastatic renal cell carcinoma (mRCC). Despite the benefit of sunitinib resistance will develop in the majority of patients. Most of them receive multiple sequential therapies during the course of disease. OBJECTIVES: To retrospectively investigate the efficacy and safety of rechallenged sunitinib in third or later line settings. PATIENTS AND METHODS: Twenty-one mRCC patients were identified who received rechallenged sunitinib between March 2010 and April 2018. Patients received sunitinib in first or second line, then other tyrosine kinase and/or mTOR inhibitors were applied, then sunitinib was rechallenged. Patients' characteristics, tolerability, treatment modalities, and treatment outcomes were recorded. The primary end-point was progression-free survival (PFS) of rechallenged sunitinib. RESULTS: Median age of patients was 62 years at the start of sunitinib rechallenge. Sixty-seven percent of patients were male. All patients had prior nephrectomy. Upon rechallenge 4 patients achieved partial response and 12 stable disease. The median PFS of first sunitinib treatment was 22 (95% CI 17-26) months and for rechallenged sunitinib 14 (95% CI 6-20) months. No increased severity of prior toxicity or new adverse events was reported during rechallenged sunitinib. The median overall survival (OS) from the start of first sunitinib was 67 (95% CI 46-76) months. Multivariate Cox regression analysis revealed that younger age (< 57 years) at start of first sunitinib (HR = 0.24; 95% CI 0.07-0.79; p = 0.019) and longer (> 2 years) first sunitinib treatment (HR = 0.28; 95% CI 0.09-0.93; p = 0.038) were independent markers of longer OS. CONCLUSION: Sunitinib rechallenge is a feasible and tolerable option with clinical benefit in selected mRCC patients.

ERG expression can predict the outcome of docetaxel combinedwith androgen deprivation therapy in metastatic hormone-sensitiveprostate cancer.

BACKGROUND: Our study aimed to analyze the potential association between clinical parameters and ERG expression and the outcome of docetaxel chemotherapy among patients with metastatic hormone-sensitive prostate cancer. PATIENTS AND METHODS: Fifty-five patients with metastatic hormone-sensitive prostate cancer were treated with docetaxel in addition to androgen deprivation therapy. Patient characteristics, clinical factors, and tumor expression of ERG by immunohistochemistry were analyzed with respect to therapeutic response and survival data. RESULTS: Relapse free survival (RFS) and overal survival (OS) were 10.5 and 40.4 months, respectively, and both correlated with PSA response (RFS: 16.8 with a ≥50% decrease in PSA vs. 5.9 months in the case of <50% decrease, P < 0.001; OS: 40.4 vs. 11.6 months, respectively, P < 0.001). There was an association between OS and early progression (OS: 40.4 months with progression after 12 months vs. 17.9 months with progression within 12 months, P = 0.009). ERG expression was detected in 21 (42%) samples. ERG positivity was associated with favorable RFS (ERG pos. vs. neg.: 26.0 vs. 11.4 months, P = 0.003). CONCLUSION: ERG expression may have a potential predictive value with respect to the effectiveness and outcome of docetaxel chemotherapy combined with androgen deprivation therapy.

Outcome of Restarted Sunitinib Treatment in Patients with Metastatic Renal Cell Carcinoma: a Retrospective Trial and Combined Case Reports from Literature.

In practice it is still not clear whether a drug holiday in sunitinib (Su) treatment can be safety, without impairing the overall outcome of patients with metastatic renal cell carcinoma (mRCC). The aim was to retrospectively evaluate the outcome in patients who restarted Su after an interruption of ≥3 months and a combined analysis of case studies from literature. From 556 patients treated between January 2006 and March 2016 a group of 38 patients were selected whose treatment was interrupted for other reasons than disease progression. During interruption Su was restarted in case of RECIST-defined progression. The primary objective was the objective response (OR) and progression free survival (PFS) of baseline and restarted therapy. The secondary objective was the overall survival (OS) calculated from the start of baseline treatment. Multivariate survival analysis was also applied. The major causes of interruption were toxicity (39%) and patient' choice (24%). Median duration of interruption was 7 (range 3-41) months. The OR of baseline and restarted treatment was 63% and 39%, respectively. After a median follow-up of 76 (95% CI 65-79) months the median PFS of baseline and restarted treatment was 21 (18-27) and 14 (10-18) months, respectively. The median OS was 61 (56-80) months. In multivariate analysis the lack of OR of restated treatment was an independent predictor of shorter PFS of restarted Su. According to our findings and also on combined case studies from literature restarted Su can be effective in selected cases of patients who progressed during treatment holiday.

Abiraterone acetate + prednisolone treatment beyond prostate specific antigen and radiographic progression in metastatic castration-resistant prostate cancer patients.

OBJECTIVES: To investigate the overall survival (OS) of chemotherapy refractory patients with metastatic castration-resistant prostate cancer who were treated with abiraterone acetate + prednisolone (AA + P) beyond prostate specific antigen (PSA) and radiographic progression (PRP) until clinical progression in comparison to patients treated until PRP. METHODS: At our institute the AA + P treatment started in 2011 in an early-access protocol trial. In October 2012 AA became generally available. From April 2011 to November 2014, 116 patients received AA + P. The clinical trial patients (T; n = 56) were treated beyond PRP until clinical progression. In the nonclinical trial group (NT; n = 57) the treatment was covered until PRP. Three patients are still under treatment. The 2 groups were statistically homogeneous, except AA + P treatment duration. The primary objective was the OS and the secondary the PSA progression-free and radiographic progression-free survivals. RESULTS: The median OS was significantly longer (P<0.0001) in the T group compared to the NT group: 21.9 (95% CI: 16.9-25) vs. 12.5 (9.3-14.1) months, respectively. In univariate analysis there were 11 parameters, which significantly affected OS, but in multivariate Cox analysis only alkaline phosphatase (AP) level at the start of treatment, systemic therapy after AA + P and cohort type (T or NT) proved to independently influence the OS. The progression-free survival curves of T and NT groups did not differ significantly. CONCLUSIONS: In our retrospective analysis low levels of AP at the start of treatment, systemic therapy applied after AA + P and treatment beyond PRP proved to be independent factors of longer OS in metastatic castration-resistant prostate cancer.

[The role of steroids in oncological practice]. / Szteroidok szerepe az onkológiai gyakorlatban.

Corticosteroids are a class of steroid hormones that are produced and disengage in the adrenal cortex. Traditionally natural and synthetic corticosteroids are used for diagnosing and treating dysfunctions of the adrenal cortex and treating inflammatory and immunological diseases. Their use is also widespread in oncological practice. Corticosteroids are indispensable in palliative care, in certain urgent oncological cases, as premedication of some chemotherapies and last but not least they have a key role in the secondary hormonal manipulations of metastatic castrate-resistant prostate cancer. The purpose of our review is to describe and compare the effects of different agents in oncological practice, to give a detailed account of the above mentioned indications and would also like to draw attention to the possible side effects of a long-term steroid treatment. Orv Hetil. 2017; 158(42): 1651-1657.

[Androgen receptor-mediated processes in castrate-resistant metastatic prostate cancer]. / Androgénreceptor mediálta folyamatok metasztatikus kasztrációrezisztens prosztatadaganatban.

In the past six years, five new drugs have been approved by the FDA for the treatment of metastatic castrate-resistant prostate cancer. While the disease itself still remains incurable, the sequential use of these drugs can significantly prolong survival while maintaining good quality of life. Research from the past decade made it clear that androgen receptor-mediated processes play a central part in the progression of the disease. Hormonal mechanisms related to androgen-receptors can remain active until late stages of the disease. A deeper understanding of these mechanisms has led to the introduction of new endocrine therapies, which resulted in a change of the nomenclature. The identification and remodelling of androgen receptor mutations that are responsible for primary and secondary resistance developing during the new therapies can pave the way to new and more efficient androgen receptor inhibitor treatments. The aim of the review is to present the pathophysiology of the androgen receptor signaling axis at the receptor level, to review FDA-approved drugs and to draw attention to the most promising developments in the treatment of this disease. Orv. Hetil., 2017, 158(2), 42-49.

[Immunotherapy in the treatment of genitourinary cancers]. / Immunterápia az urológiai daganatok kezelésében.

In this clinical review we provide information regarding advance and main achievements in the immunotherapy of genitourinary, particularly renal cell and prostate cancer. Nivolumab treatment became the new standard of care in locally advanced or metastatic renal cell cancer after failure on tyrosine kinase inhibitor treatment. Sipuleucel-T prolonged survival in patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer but had no effect on progression-free survival. Based on the results of phase I/II trials anti-PD-1/PD-L1 monoclonal antibodies are a new hope in the treatment of urothelial bladder cancer. Regarding germ cell tumors basic research is ongoing.

Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma.

BACKGROUND: The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. PATIENTS AND METHODS: 274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides χ(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used. RESULTS: The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment-associated AEs. Significantly longer (P < .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P < .001) and overall survival (P < .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P < .001) and mOS (51 vs. 9 months, respectively; P < .001). CONCLUSION: Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment.

[Role of targeted therapy in the treatment of squamous cell head and neck cancer]. / Célzott kezelés lehetôségei a laphámsejtes fej-nyaki daganatok kezelésében.

Epidermal growth factor receptor (EGFR) is highly expressed in head and neck cancer (HNC). Since EGFR has a large extracellular ligand binding as well as an intracellular tyrosine kinase domain, anti-EGFR therapy may involve anti-ligand binding domain antibody- or tyrosine kinase inhibitor therapies. Phase II-III studies confirmed the efficacy of anti-EGFR antibody therapy in case of squamous cell HNC. In combination with irradiation, anti-EGFR antibody therapy improved survival of locally advanced HNC patients. In case of recurrent or metastatic HNC, anti-EGFR antibody therapy in combination with chemotherapy significantly increased remission rate without increasing toxicity. Although studies on EGFR kinase inhibitors in HNC are in early phase, preliminary data are encouraging.

Influence of thymidylate synthase gene polymorphisms on the survival of colorectal cancer patients receiving adjuvant 5-fluorouracil.

The present study aimed to prospectively investigate the influence of thymidylate synthase (TS) polymorphisms (5'-TSER, 3'-TSUTR) on the disease-free survival (DFS) and overall survival (OS) of patients with colorectal cancer (CRC) who were treated with adjuvant 5-fluorouracil (5-FU) therapy. Patients were followed up for 19+/-14 months (median+/-SD). TS genotypes were determined from the peripheral blood mononuclear cells of 166 patients by polymerase chain reaction-polyacrylamide gel electrophoresis and restriction fragment length polymorphism methods. 5'-TSER 3R homozygotes showed significantly longer DFS (P = 0.048) and OS (P = 0.009). The 5'-TSER and 3'-TSUTR genotype combination groups showed a significant difference for DFS (P = 0.039) and OS (P = 0.029). Significantly better DFS (P = 0.049) and OS (P = 0.043) were observed for 6 bp/6 bp genotypes in 5'-TSER heterozygotes (n = 80). Based on this, and on hazard ratios obtained by Cox regression analysis of the DFS of genotype-combinations, the patients were classified as belonging to prognostic groups A and B. The DFS and OS of these two groups showed a highly significant difference (P = 0.002 and 0.001). In the multivariate Cox regression model, beside tumour location, the prognostic classification (groups A and B) proved to be an independent prognostic factor. Our data suggest that those TS genotypes and their combinations (group A: 3R/3R with any 3'-TSUTR genotype and 2R/3R with 6 bp/6 bp), which have been reported earlier as having high TS expression, predict significantly longer DFS and OS. We found that a combination of germline TS polymorphisms is an independent prognostic marker in selecting CRC patients with worse prognosis, and it may be worthwhile to examine whether these patients would benefit from an alternative therapy.

[The clinical importance of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the 5-fluoropyrimidine-based therapy of metastatic colorectal tumours]. / A metiléntetrahidrofolát-reduktáz (MTHFR) C677T polimorfizmus klinikai jelentôsége a metasztatikus colorectalis daganatok 5-fluoropirimidin-alapú kezelésében.

The authors investigated the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in 101 metastatic colorectal cancer patients treated with 5-fluoropyrimidine-based therapy and in 196 healthy individuals by PCR-RFLP method. There was no significant difference in genotype distribution of patients and healthy controls, and between subgroups investigated according to clinical parameters (age, gender, tumor location, grade and treatment type). However, after a 3-30 (median 18.5) months follow-up the survival of patients with T allele proved to be better than that of patients with wild type (CC) genotype (p=0.036). In case of CT and TT genotypes the survival of patients receiving only first line therapy was significantly shorter than that of patients receiving more lines of treatment (p=0.015). Determination of MTHFR C677T polymorphism has prognostic value in case of patients with metastatic colorectal cancer receiving 5-fluoropyrimidine-based therapy, and may help in designing the individual (group) tailored therapy.