Vera Miskovska

Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study

PURPOSE Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. METHODS Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon Dophilus™, was administered at a dose of 10×10(9)CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. RESULTS Twenty-three patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p=0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p=0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. CONCLUSIONS Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity.

Phase II study of everolimus in refractory testicular germ cell tumors

BACKGROUND Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs. METHODS From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors. RESULTS No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1-35.1mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression-free survival was 1.7 months (95% CI: 1.1-4.0mo) and median overall survival was 3.6 months (95% CI: 2.0-11.0mo). CONCLUSIONS This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs. CONDENSED ABSTRACT Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients.

The prognostic value of DNA damage level in peripheral blood lymphocytes of chemotherapy-naïve patients with germ cell cancer

Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to toxic effects of CDDP-based chemotherapy. This study was aimed to evaluate the prognostic value of DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. PBLs isolated from 59 chemotherapy-naïve GCT patients were included into this prospective study. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage tail DNA by the Metafer-MetaCyte analyzing software. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 5.25 ± 0.64. Patients with DNA damage levels lower than mean had significantly better progression free survival (hazard ratio [HR] = 0.19, 95% CI (0.04 – 0.96), P = 0.01) and overall survival (HR = 0.00, 95% CI (0.00 – 0.0), P < 0.001) compared to patients with DNA damage levels higher than mean. Moreover, there was significant correlation between the DNA damage level and presence of mediastinal lymph nodes metastases, IGCCCG (International Germ Cell Cancer Collaborative Group) risk group, and serum tumor markers level. These data suggest that DNA damage levels in PBLs of GCT patients may serve as an important prognostic marker early identifying patients with poor outcome.

Prognostic value of serum carbonic anhydrase IX in testicular germ cell tumor patients

Despite the fact that testicular germ cell tumors (TGCTs) are one of the most chemosensitive solid tumors, a small proportion of patients fail to be cured following cisplatin-based first line chemotherapy. Upregulation of carbonic anhydrase IX (CA IX) in various solid tumors is associated with poor outcome. The current prospective study investigated the prognostic value of serum CA IX level in TGCTs. In total, 83 patients (16 non-metastatic following orchiectomy with no evidence of disease, 57 metastatic chemotherapy-naïve and 10 metastatic relapsed chemotherapy-pretreated) starting adjuvant and/or new line of chemotherapy and 35 healthy controls were enrolled in the study. Serum CA IX values were determined using an enzyme-linked immunosorbent assay, and intratumoral CA IX was analyzed by immunohistochemistry. Metastatic chemotherapy-naïve patients had significantly higher mean CA IX serum levels than healthy controls (490.6 vs. 249.6 pg/ml, P=0.005), while there was no difference in serum CA IX levels in non-metastatic or relapsed TGCT patients compared with healthy controls. There was no significant difference in the mean serum CA IX levels between different groups of patients and between the first and second cycle of chemotherapy, nor association with patients/tumor characteristics. Serum CA IX was not prognostic for progression-free survival [hazard ratio (HR)=0.81, P=0.730] or overall survival (HR=0.64, P=0.480). However, there was a significant association between intratumoral CA IX expression and serum CA IX concentration (rho=0.51, P=0.040). These results suggest that serum CA IX level correlates with tumor CA IX expression in TGCT patients, but fails to exhibit either a prognostic value or an association with patients/tumor characteristics.

Abstract 4704: Correlation between serum cytokine/angiogenic factors (CAFs) and tumor markers in testicular germ cell tumor patients.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: There is an unmet need for noninvasive markers to identify patients with TGCTs most likely to benefit from treatment and to measure the effects of therapies. Cytokines can be easily identified and they have an important role on tumor initiation, growth, and progression. Prognostic and predictive values of 52 plasma CAFs in patients with metastatic renal cell carcinoma were recently investigated. Our endpoint was to find out relationship between established tumor markers beta-human choriogonadrotropin (HCG) and alphafetoprotein (AFP) with CAFs. Methods: We enrolled 47 patients with TGCTs treated by 1st line platinum based systemic chemotherapy. All patients received G-CSF support after chemotherapy (44 patients pegfilgrastim, 3 patients filgrastim). Fifty one plasma CAFs were analyzed before the 1st (47 patients) and before the 2nd cycle of chemotherapy (22 patients) using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system, Bio-Rad Laboratories, Hercules, CA). HCG and AFP were measured by enhanced chemiluminescence immunoassay. CAFs were correlated to pretreatment serum levels of HCG and AFP. Spearmans correlation test was used to analyze the relationship between CAFs and tumor markers. We considered p <0.05 to be significant. Results: Median pretreatment AFP and HCG were 2.6 U/ml (range 0.9-13936.0 U/ml) and 5.5 mIU/ml (range 0.0-564261.0 mIU/ml), respectively. By the correlation analyses 4 from 51 pretreatment plasma CAFs were negatively and one positively correlated to pretreatment AFP. Negatively correlated CAFs were TGF-b1 (p=0.041), TGF-b3 (p=0.040), IL-7 (p=0.039) and G-CSF (p=0.016), positive correlation between pretreatment MIF (p=0.005) and pretreatment values of AFP was observed. We investigated, that pretreatment HCG had positive correlation to IL-2Ra (p=0.031), MIG (p=0.015), SCGF-b (p=0.045) and b-NGF (p=0.017), there was no negative elevation of pretreatment CAFs in correlation with pretreatment HCG. Additionally, we calculated ratio between pretreatment and postreatment values of CAFs. We investigated, that pretreatment HCG positively correlated to ratio values of several CAFs (IL-2Ra, p=0.009; IL-16, p=0.046; IL-18, p=0.014; SCGF-b, p=0.018; CTACK, p=0.004) and pretreatment AFP to RANTES (p=0.035), no negative relationships were observed. Conclusions: Several serum CAFs with significant correlation to pretreatment AFP and HCG were identified in this study. We suppose that this finding may be useful for further investigations, biological and clinical consequences of this correlation have to be find out. This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0016-11. Citation Format: Daniela Svetlovska, Michal Mego, Dana Cholujova, Paulina Gronesova, Patrik Palacka, Usakova Vanda, Vera Miskovska, Bibiana Vetrakova-Krakovska, Jan Luha, Jozef Mardiak. Correlation between serum cytokine/angiogenic factors (CAFs) and tumor markers in testicular germ cell tumor patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4704. doi:10.1158/1538-7445.AM2013-4704