In a phase 3 clinical trial involving previously treated patients with advanced renal-cell carcinoma, progression-free survival was significantly longer with the VEGF receptor inhibitor cabozantinib ...than with everolimus (7.4 months vs. 3.8 months).
Renal-cell carcinoma is the most common form of kidney cancer, with more than 330,000 cases diagnosed and more than 140,000 deaths attributed to it worldwide every year.
1
Approximately one third of patients present with metastatic disease at diagnosis,
2
and in about one third of treated patients with localized disease, the disease will relapse.
3
–
5
Inactivation of the von Hippel–Lindau (VHL) tumor-suppressor protein characterizes clear-cell tumors, the predominant histologic subtype in patients with renal-cell carcinoma, and results in the up-regulation of vascular endothelial growth factor (VEGF) production.
6
,
7
Antiangiogenic drugs that target VEGF (bevacizumab) and its receptors (sunitinib, sorafenib, pazopanib, and . . .
Purpose Cabazitaxel 25 mg/m
(C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) ...in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m
(C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of ≥ 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained ≥ 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20.
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).
Preventing the ototoxicity caused by cisplatin is a major issue yet to be overcome. Useful preventive treatments will soon be available. Consequently, the next step is to filter out those patients ...who are more prone to develop ototoxicity. The aim of this study was to prospectively evaluate potential predictive markers of acute ototoxicity as determined by measures of distortion product otoacoustic emissions (DPOAEs). A total of 118 patients from our previous DPOAE analysis were put under evaluation. Ototoxic cases were divided according to unilateral (
n
= 45) or bilateral (
n
= 23) involvement. The clinicopathological characteristics, hearing test results, germline
GSTT1
,
GSTM1
, and
GSTP1
polymorphisms, and common laboratory parameters were included in the new analysis. Univariate and multivariate statistical tests were applied. According to multivariate logistic regression, the only independent predictor of unilateral ototoxicity (vs. non-affected) was a
GSTM1
null genotype (OR = 4.52; 95%CI = 1.3–16.3), while for bilateral damage, the
GSTT1
null genotype (OR = 4.76; 1.4–16) was a predictor. The higher starting serum urea level was characteristic of bilateral ototoxicity; however, the only independent marker of bilateral (vs. unilateral) ototoxicity was the presence of
GSTT1
null genotype (OR = 2.44; 1.23–4.85). Different processes, involving the
GSTM1
and
GSTT1
genotypes, respectively, govern the development of acute unilateral and bilateral ototoxicities. Further research is needed to clarify these processes. Based on the above findings, patients whom are at risk may be selected for otoprotective therapies.
Key messages
The acute ototoxicity was determined by DPOAE in 118 testicular cancer patients.
GSTM1
null was the only marker of unilateral ototoxicity (vs. non-affected).
The only marker of bilateral hearing loss (vs. non-affected) was the
GSTT1
null.
GSTT1
null was also the marker of bilateral vs. unilateral ototoxicity.
A high-risk group may be selected for new, individualized otoprotective treatment.
Lung cancer is the leading cause of cancer related mortality all over the world, and a number of developments have indicated future clinical benefit recently. The development of molecular pathology ...methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. The most significant changes in the treatment of NSCLC revealed in new pathologic classification and in the introduction of molecularly targeted therapies, which include monoclonal antibodies and small molecule tyrosine kinase inhibitors. The side effects of these agents are generally better tolerated than those of conventional chemotherapy and show higher efficacy. The most important factor follows: histology subtypes, gene mutation status, patients’ selection, drug toxicities and occurence of drug resistance. In the advanced disease, the hope of cure is less than 3 %, but improvements in survival have been clearly achieved. Some years ago the median lung cancer survival rate was 10–12 months, now in case of available specific molecular targets, a significant increase in median survival rates to 24–36 months has been achieved. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. This review focuses on the rationale for targeted agents and new treatment possibilities in case of advanced lung adenocarcinoma.
Abstract
Background
In Hungary, the mortality rate for testicular germ cell cancer (TGCC) is 0,9/100000 which is significantly higher than the EU average. We prospectively evaluated the effect of ...socioeconomic position on patient delay and therapy outcomes.
Methods
Questionnaires on subjective social status (MacArthur Subjective Status Scale), objective socioeconomic position (wealth, education, and housing data), and on patient’s delay were completed by newly diagnosed TGCC patients.
Results
Patients belonged to a relatively high socioeconomic class, a university degree was double the Hungarian average, Cancer-specific mortality in the highest social quartile was 1.56% while in the lowest social quartile 13.09% (
p
= 0.02). In terms of patient delay, 57.2% of deceased patients waited more than a year before seeking help, while this number for the surviving patients was 8.0% (
p
= 0.0000). Longer patient delay was associated with a more advanced stage in non-seminoma but not in seminoma, the correlation coefficient for non-seminoma was 0.321 (
p
< 0.001). For patient delay, the most important variables were the mother’s and patient’s education levels (r = − 0.21,
p
= 0.0003, and r = − 0.20,
p
= 0.0005), respectively. Since the patient delay was correlated with the social quartile and resulted in a more advanced stage in non-seminoma, the lower social quartile resulted in higher mortality in non-seminoma patients (
p
= 0.005) but not in seminoma patients (
p
= 0.36) where the patient delay was not associated with a more advanced stage.
Conclusions
Based on our result, we conclude that to improve survival, we should promote testicular cancer awareness, especially among the most deprived populations, and their health care providers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Targeted therapies significantly improve clinical outcomes among patients with metastatic renal cell carcinoma (mRCC). Several new agents have been approved for first- and second-line use. ...However, there is a lack of compelling evidence comparing sequencing strategies, and available comparative data regarding the real-world effectiveness of different therapeutic sequences are limited.
Materials and Methods
We identified mRCC patients who initiated targeted therapy between January 1, 2008 and May 31, 2017 from the National Health Insurance Fund (NHIF) database of Hungary. Overall survival (OS) and duration of first-line treatment (DFT) were obtained for patients receiving sunitinib-everolimus, sunitinib-axitinib, or pazopanib-everolimus treatment sequences. OS of sunitinib-everolimus and sunitinib-axitinib sequences was also determined for patients having better or worse response to sunitinib first-line therapy.
Results
Median OS was significantly longer among patients treated with sunitinib-axitinib compared to those receiving sunitinib-everolimus. Median DFT was also significantly longer in the sunitinib-axitinib vs. sunitinib-everolimus group. Sunitinib-axitinib was associated with significantly longer median OS compared to sunitinib-everolimus in patients with better response to first-line sunitinib in the pooled sunitinib population. In patients with worse response to sunitinib, sunitinib-axitinib was associated with a trend towards greater OS compared to sunitinib-everolimus, but the difference did not reach statistical significance.
Conclusions
In this nationwide database analysis, mRCC patients treated with the sunitinib-axitinib sequence had significantly longer OS compared to those receiving sunitinib-everolimus therapy. The OS benefits of second-line axitinib were consistent among patients with better response to sunitinib defined by DFT values.
Background The use of checkpoint inhibitors has become increasingly important in the treatment of different cancers, including advanced muscle-invasive urothelial cancer and even in basal cell ...carcinoma. We present the case of a patient with advanced basal cell carcinoma and metastatic muscle-invasive urothelial cancer, who was treated with the programmed death-ligand 1 inhibitor, atezolizumab for both cancers. Case presentation A 72-year-old Caucasian female patient, with a history of smoking without any comorbidities developed periocular basal cell carcinoma, which was surgically removed but relapsed 4 years later. Surgical excision was carried out twice, but with positive margins, therefore definitive radiotherapy was given. Subsequently, the patient developed non-muscle-invasive papillary urothelial carcinoma, which was removed by transurethral resection. Follow-up was irregular owing to the patient's inadequate compliance, and within 2 years, the patient's cancer relapsed and histology confirmed muscle-invasive urothelial carcinoma. Definitive radiochemotherapy was not accepted by the patient. Meanwhile, the patient's basal cell carcinoma had also progressed, despite receiving vismodegib therapy. Therefore, the patient was administered epirubicin-cisplatin. Having reached the maximum cumulative dose of epirubicin, treatment with this chemotherapeutic agent could not be continued. The patient developed bladder cancer metastasis in her left suprainguinal lymph nodes. Owing to the presence of both types of tumors, programmed death-ligand 1 inhibitor atezolizumab treatment was chosen. In just over 1 year, the patient received 17 cycles of atezolizumab altogether, which was tolerated well without any adverse or side effects. Follow-up imaging scans indicated complete remission of the metastatic bladder cancer and stable disease of the basal cell carcinoma. The patient subsequently passed away in hospital due to a complication of COVID-19 infection. Conclusions Our patient attained stable disease in advanced basal cell carcinoma and complete remission in metastatic muscle-invasive urothelial cancer after receiving programmed death-ligand 1 inhibitor, atezolizumab, therapy. To our knowledge, this is the first paper to report the use of programmed death-ligand 1 inhibitor, atezolizumab, as treatment for advanced basal cell carcinoma. This case may also be of interest for clinicians when treating patients with two synchronous cancers. Keywords: Advanced basal cell carcinoma, Metastatic muscle-invasive bladder cancer, PD-L1 inhibitor, Checkpoint inhibitor, Atezolizumab
Due to its palindromic setup, AZFc (Azoospermia Factor c) region of chromosome Y is one of the most unstable regions of the human genome. It contains eight gene families expressed mainly in the ...testes. Several types of rearrangement resulting in changes in the cumulative copy number of the gene families were reported to be associated with diseases such as male infertility and testicular germ cell tumors. The best studied AZFc rearrangement is gr/gr deletion. Its carriers show widespread phenotypic variation from azoospermia to normospermia. This phenomenon was initially attributed to different gr/gr subtypes that would eliminate distinct members of the affected gene families. However, studies conducted to confirm this hypothesis have brought controversial results, perhaps, in part, due to the shortcomings of the utilized subtyping methodology. This proof-of-concept paper is meant to introduce here a novel method aimed at subtyping AZFc rearrangements. It is able to differentiate the partial deletion and partial duplication subtypes of the Deleted in Azoospermia (DAZ) gene family. The keystone of the method is the determination of the copy number of the gene family member-specific variant(s) in a series of sequence family variant (SFV) positions. Most importantly, we present a novel approach for the correct interpretation of the variant copy number data to determine the copy number of the individual DAZ family members in the context of frequent interloci gene conversion.Besides DAZ1/DAZ2 and DAZ3/DAZ4 deletions, not yet described rearrangements such as DAZ2/DAZ4 deletion and three duplication subtypes were also found by the utilization of the novel approach. A striking feature is the extremely high concordance among the individual data pointing to a certain type of rearrangement. In addition to being able to identify DAZ deletion subtypes more reliably than the methods used previously, this approach is the first that can discriminate DAZ duplication subtypes as well.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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