Carcinoid syndrome with right-sided valve involvement - a case report and review of the literature.

BACKGROUND: The survival of patients with neuroendocrine tumors has substantially improved with modern treatment options. Although the associated carcinoid syndrome can be diagnosed early and controlled effectively, cardiologists still encounter patients with cardiac manifestations, particularly among individuals with persistently high levels of vasoactive mediators. Treatment options have been limited to surgical valve replacement in fully manifested disease. Since surgery is not always feasible, transcatheter valve implantation is becoming an interesting alternative. CASE: A case of a 50-year-old woman with carcinoid syndrome and right-sided valvular heart disease is presented. Moderate pulmonary valve stenosis and severe tricuspid valve regurgitation were diagnosed during the evaluation and treatment of neuroendocrine tumor. The possibility of rare valve involvement and the need for interdisciplinary cooperation in the diagnosis, monitoring and treatment of patients with neuroendocrine tumors producing vasoactive substances must be emphasized. CONCLUSION: The patient had a typically presenting carcinoid syndrome with a rare cardiac manifestation. Although monitoring and treatment were carried out in accordance with recommendations and appropriate to the clinical condition, rapid progression of the metastatic disease ultimately precluded invasive cardiac intervention.

Appendiceal tumors and pseudomyxoma peritonei: current recommendations for clinical practice.

Appendiceal tumors and pseudomyxoma peritonei (PMP) are rare tumors. Perforated epithelial tumors of the appendix are the most common source of PMP. This disease is characterized by the presence of mucin of varying degrees of consistency, partially adherent to the surfaces. Appendiceal mucoceles themselves are also very rare and usually their treatment involves only a simple appendectomy. The aim of this study was to provide an up-to-date review of the recommendations for the diagnosis and treatment of these malignancies according to the current guidelines of The Peritoneal Surface Oncology Group International (PSOGI) and the Blue Book of the Czech Society for Oncology of the Czech Medical Association of J. E. Purkyne (COS CLS JEP).

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Cabozantinib in the treatment of metastatic renal cell carcinoma - final data analysis from four oncology centers in the Czech Republic.

BACKGROUND: Current standard treatments for patients with metastatic renal cell carcinoma (mRCC) involve tyrosine kinase inhibitors (TKI) that inhibit angiogenesis. Cabozantinib is a multi TKI used for the treatment of mRCC in the first- and second-line setting. PURPOSE: The aim of this study was the final analysis of treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib after previous targeted therapy. PATIENTS AND METHODS: A total of 54 patients with mRCC from four oncology centers in the Czech Republic were evaluated retrospectively; the median follow-up was 18.5 months. Cabozantinib was administered in a dose of 60mg/day, a subset of patients received an initial dose of 40mg/day. The treatment was administered until the progression. The Kaplan-Meier analysis was used to calculate progression free survival (PFS) and overall survival (OS). We performed a multivariate analysis of risk factors for treatment outcomes (PFS, OS) by regression analysis. All statistics were evaluated at the significance level α = 0.05. RESULTS: The median PFS in all patients was 9.3 months (95% CI 7.2 - 11.4). The median OS in all patients was 21.9 months (95% CI 15.5 - 28.4). The median PFS in patients with bone metastases was not statistically significantly different compared with patients without bone metastases (9.3 vs 8.7 months, P = 0.53). The median OS in patients with bone metastases was statistically significantly shorter compared with patients without bone metastases (17.7 vs 26.8 months, P = 0.021). A treatment response was observed in 40.7 % of cases, including one complete remission. The regression analysis demonstrated a significant effect on OS in patients with the presence of subsequent treatment (P = 0.001), patients with treatment duration of first line therapy 6 months (P = 0.019) and 12 months (P = 0.003) and in patients without bone metastases (P = 0.021). CONCLUSION: Our final analysis of patients with mRCC treated with cabozantinib after previous targeted therapy confirmed its effectiveness.

Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study.

BACKGROUND: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. PATIENTS AND METHODS: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan-Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. RESULTS: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). CONCLUSIONS: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Changes in expression of lysosomal membrane proteins in leucocytes of cancer patients treated with tyrosine kinase inhibitors.

Lysosomal sequestration of weak base drugs has been identified as one of the stress-related mechanisms that trigger in vitro lysosomal biogenesis controlled by transcription factor EB (TFEB). Whether such mechanism can induce lysosomal biogenesis in vivo is unknown. In this study, we addressed the question whether prolonged treatment with sunitinib (SUN) in patients with advanced renal cell carcinoma (n = 22) and with imatinib (IM) in those with gastrointestinal stromal tumor (n = 6) could induce lysosomal biogenesis in leukocytes. Lysosomal biogenesis was monitored using immunoblotting of three lysosomal membrane proteins: lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2) and vacuolar H+-ATPase, B2 subunit (ATP6V1B2). Present results indicate that prolonged treatment with SUN affects LAMP1 and LAMP2 expression only marginally in most patients. In contrast, changes in ATP6V1B2 expression were marked and resembled irregular oscillations. Very similar changes in the expression of lysosomal membrane proteins were also found in IM-treated patients. Conclusion: prolonged treatment of cancer patients with SUN and IM did not induce leucocyte lysosomal biogenesis but dramatically affected expression of ATP6V1B2.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Targeted axillary dissection with preoperative tattooing of biopsied positive axillary lymph nodes in breast cancer.

Sentinel lymph node biopsy (SLNB) has emerged as an alternative to axillary lymph node dissection during breast cancer surgery during the last 2 decades. However, there are several controversies regarding the indication of the sentinel node biopsy after neoadjuvant chemotherapy which can convert positive lymph nodes to negative. The false-negative rate after neoadjuvant chemotherapy is unacceptably high. This high false-negative rate can be decreased by marking of the positive lymph nodes and removal during sentinel lymph node biopsy procedure in addition to the sentinel lymph nodes. The aim of this study was to investigate the possibility of carbon tattooing of the positive sentinel lymph nodes before neoadjuvant chemotherapy. In 2016, a prospective protocol was launched investigating the black carbon tattooing procedure of the suspective and positive axillary lymph nodes by injecting 0.1-0.5 carbon ink in normal saline under ultrasound guidance. All patients underwent black carbon tattooing of the suspected or positive axillary lymph nodes before the chemotherapy or one week before the primary surgery when chemotherapy was not indicated in the neoadjuvant setting. Sentinel lymph nodes together with lymph nodes marked by the black carbon ink were removed and histologically evaluated. So far 27 patients were treated under this protocol. Breast saving surgery was performed in 22 cases and mastectomy in 5 cases. All patients had invasive ductal carcinoma. In 20 patients neoadjuvant chemotherapy was indicated and in 7 patients primary surgery was performed. All lymph nodes marked by black carbon ink were successfully identified and removed. Sentinel lymph node biopsy was performed in 8 cases and sentinel lymph node biopsy followed by axillary dissection in 15 cases. Axillary dissection alone was performed in 4 cases. In 19 cases, the black carbon ink was present in the sentinel lymph node at the same time and in 4 cases carbon dye was present in other lymph nodes than the lymph node identified during SLNB, which corresponds to 17.4%. In the group of patients undergoing primary surgery, in one case from six, the sentinel lymph node was negative and the lymph node marked with carbon ink positive which represents false-negative lymph node and failure of the SLNB procedure. After neoadjuvant chemotherapy, there was no false-negative lymph node identified, but the conversion of the positive lymph nodes to negative was present in 10 cases (50%). There were no complications attributed to carbon ink tattooing. The results of positive sentinel lymph nodes tattooing have confirmed that this method is safe and allows a decrease in the false negativity rate during the sentinel node biopsy procedure.

Association of triple positivity with prognostic parameters and overall survival in a population-based study of 6,122 HER2-positive breast cancer patients: analysis of real-world clinical practice based on a research database.

Triple-positive breast cancer (TPBC), i.e. HER2-positive (HER2+) and hormone receptors-positive breast cancer, is a specific subgroup of breast cancers. TPBC biology is characterized by strong mutual interactions between signaling pathways stimulated by estrogens and HER2 amplification. The present study aims to carry out a population-based analysis of treatment outcomes in a cohort of hormone receptor (HR) positive and negative breast cancer patients who were treated with anti-HER2 therapy in the Czech Republic. The BREAST research database was used as the data source for this retrospective analysis. The database covers approximately 95% of breast cancer patients treated with targeted therapies in the Czech Republic. The analysis included 6,122 HER2-positive patients. The patients were divided into two groups, based on estrogen receptor (ER) or progesterone receptor (PR) positivity: hormone receptor negative (HR-) patients had both ER- and PR-negative tumors (n=2,518), unlike positive (HR+) patients (n=3,604). HR+ patients were more often diagnosed premenopausal at the time of diagnosis, presented more often at stage I or II and their tumors were less commonly poorly differentiated. The overall survival (OS) was significantly higher in subgroups of HR+ patients according to treatment setting. When evaluated by stages, significantly higher OS was observed in HR+ patients diagnosed at stages II, III, and IV and regardless of tumor grade.

Metastatic Clear Cell Renal Carcinoma Without Evidence of a Primary Renal Tumour Mimicking Advanced Stage of Malignant Lung Tumour.

BACKGROUND: Clear cell renal carcinoma (ccRC) accounts for 65-70% of renal carcinomas with peak occurrence at the 6th and 7th age decade, predominantly in males. At the time of diagnosis, especially pulmonary metastases can be found in one-third of patients. There have also been described as late metastases for several decades after nephrectomy. In our case report, clinical course indicated primary lung tumour. Histological differential diagnosis included malignant pleural mesothelioma, lung adenocarcinoma and squamous cell carcinoma with clear cell differentiation or primary clear cell adenocarcinoma of the lung. However, using immunohistochemistry, all these possible diagnoses were excluded. CASE REPORT: We present a case of 62-year old man with 3 months history of progressive dyspnea accompanied with a cough and recurrent pleural effusions. PET/CT scan revealed metastatic tumour spread with right-sided pleural thickening, multiple pulmonary tumour foci, mediastinal, cervical, abdominal para-aortic and pelvic lymph node involvement and skeletal metastasis. The patient died one day after administration of palliative chemotherapy. The autopsy showed the majority of changes in the right hemithorax, was caused by a diffuse yellowish, extremely tough tumour infiltrating parietal and visceral pleura with adhesions and obliteration of truncus pulmonalis. In left lung and both renal cortices we could see scant nodules, mimicking primary lung tumour metastasis. In close proximity to the left renal hilum we found unusual homogeneous white round to oval tissue of 80 × 86 × 72mm in diameter, with identical histological pattern. Extensive immunohistochemical profile (positivity of CK18, PAX8, vimentin, androgen receptor, napsin A; negativity of mesothelial markers, TTF-1, CK7, CK20, CDX-2, CD10, PSA, CK34B12 and PAS-D) was compatible with metastatic ccRC. CONCLUSION: We present an extremely rare case of morphologically verified metastatic ccRC without evidence of primary lesion in the kidneys. There is speculated the possibility of spontaneous regression of primary tumour. In our case, however, we cannot exclude the possibility of generalized primary tumour of ectopic kidney. This hypothesis is based on the finding of isolated tumour mass adjacent to left renal hilum.

HPV Status and Mutation Analysis Using Multiparallel Sequencing in Distal Oesophageal and Gastro-oesophageal Junction Adenocarcinomas.

The incidence of adenocarcinoma of oesophagus or gastro-oesophageal junction is increasing in Europe and other regions of the Western world. Research of possible causes has shifted to the molecular level. This study evaluated human papillomavirus (HPV) using real-time PCR and mutational status of selected genes using the multiparallel sequencing method (NGS) in DNA extracted from paraffin-embedded tumour tissue of 56 patients with oesophageal or gastro-oesophageal junction adenocarcinoma. The genetic material was in sufficient quality for the analysis in 37 cases (66 %). No HPV-positive sample was found. NGS revealed higher frequency of mutations in TP53, ARID1A, PIK3CA, SMAD4, ERBB2, MSH6, BRCA2, and RET genes. Association between gene mutations and histological grade, subtype according to Lauren, or primary tumour site was not statistically significant. In conclusion, the study did not confirm any HPV-positive sample of oesophageal and gastro-oesophageal junction adenocarcinoma. The study confirmed the usefulness of NGS analysis of paraffin-embedded tissue of these tumours, and it could be used in clinical studies to evaluate the prognostic and/or predictive value of the tested mutations. The association between gene mutations and histological features should be tested in larger patient cohorts.

Complications and mortality of surgical therapy for esophageal cancer: 10 years single center experience.

A single-center retrospective study the complication and mortality of surgical treatment of esophageal cancer 2006 to 2015 is presented. A total of 212 patients with esophageal cancer were operated at the First Department of Surgery University Hospital Olomouc, Czech Republic in the period between 2006 and 2015. Adenocarcinoma was histologically described in 127 patients (59.9%), squamous cell carcinoma in 82 patients (38.7%), and other types of carcinoma were described in 3 cases. According to the preoperative staging of esophageal cancer, the patients with early stage disease (T1-2N0M0) had primary surgery, while the patients with advanced stage (T3-4N0-2M0) were indicated for neoadjuvant chemoradiation with the surgery being performed subsequently. Transhiatal laparoscopic esophagectomy was performed in 183 patients, and Orringer esophagectomy in 4 patients. Thoracoscopic esophagectomy was performed in 17 patients and thoracotomy in 30 patients. Respiratory failure with the development of ARDS syndrome accompanied by multiple-organ failure occurred in 21 patients. Statistically significant association between mortality and ASA (p = 0.009) and between respiratory complications and ASA (p = 0.006) was demonstrated. The majority of patients who died were under 60 years of age (p = 0.039). Further, significant association between 30-day mortality and tumor stage (p = 0.021), gender (p = 0.022) and age (p = 0.018) was evident. A significant association between tumor stage and fistula in anastomosis, (p = 0.043) was observed. Esophagectomy is a procedure, which should be performed in specialized high-volume centers experienced in treatment of this serious malignancy and by certified oncology surgeons with long time experience in esophageal surgery.

[Combined Regimens in Immunotherapy]. / Kombinované rezimy v imunoterapii.

The advent of immunotherapy has changed our concept of how to manage metastatic disease. With the exception of relatively rare tumors, the treatment of metastatic cancer is still considered as palliative, and in systemic treatment immunotherapy is often selected, considering better tolerance. Immunotherapy opens the perspective of a long-term, possibly durable, response, and, in contrast to other approaches to targeted therapy, is active across a spectrum of tumors. Combined regimens that increase the efficacy, given the context, are thus of importance. The most promising results are currently obtained using a combination of ipilimumab and nivolumab for the treatment of metastatic malignant melanoma and metastatic renal cell carcinoma. Toxicity of the treatment can be managed by supportive care, and combination immunotherapy is gradually becoming established as a standard option in the management of these two neoplastic disorders. Moreover, additional trials using a combination of ipilimumab and nivolumab to treat other tumors are underway as well as studies of other combinations, including those that employ antibodies acting on immune checkpoints in combination with other targeted agents or cytotoxic chemotherapy. Other options include combinations with surgical therapy, i.e., adjuvant or neoadjuvant administration of immunotherapy or with radiotherapy based on the abscopal effect of radiation. Thus, although the results of combination immunotherapy are very promising, this strategy is still in its infancy. Thus, only the next generation of clinical trials will be able to determine to what extent these combined regimens can meet the high expectations of medical oncologists and the general public.Key words: immunotherapy - ipilimumab - nivolumab - pembrolizumab The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 27. 9. 2017Accepted: 3. 10. 2017.

[Evaluation of Anti-cancer Therapies with Reimbursement Limited to Comprehensive Cancer Centres Using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale]. / Hodnocení klinického benefitu protinádorových léku limitovaných na komplexní onkologická centra podle metodiky ESMO-MCBS.

BACKGROUND: The costs of oncology treatments are increasing, due to the rising prevalence of malignant diseases and the introduction of expensive novel anti-cancer agents. The new European Society for Clinical Oncology (ESMO) has recently developed a new parametric system to evaluate the clinical benefit of drugs. The Magnitude of Clinical Benefit Scale (ESMO-MCBS) compares the contribution of a novel drug based on overall and progression-free survival and quality of life with those of current treatment options. MATERIAL AND METHODS: An expert group of the Czech Oncological Society conducted an assessment based on published data and an ESMO-MCBS methodology for antineoplastic agents used for the treatment of solid tumors with limited reimbursement to Comprehensive Cancer Centers. We evaluated drugs categorized as "S" that were eligible for public health insurance as of January 1, 2017. RESULTS AND CONCLUSION: The ESMO-MCBS score is a promising new parameter for the evaluation of new anticancer drugs. The ESMO-MCBS method for assessing the clinical benefit of drugs is simple, robust, and reproducible. The advantage of the assessment is that it is not based on a single index but rather combines several dimensions of drug performance. This parameter will be gradually added to Czech cancer guidelines. Scores obtained in the majority of cases correspond to the observed benefit of a drug in routine clinical practice.Key words: tumors - farmacotherapy - assesment study as a subject - survival - protocols of anti-cancer therapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 3. 5. 2017Accepted: 20. 6. 2017.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer.

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer.

BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). RESULTS: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. CONCLUSIONS: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. CLINICAL TRIAL REGISTRY AND TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00719264.