[Show abstract][Hide abstract] ABSTRACT: Malnutrition affects a large part of patients with malignant neoplasm. Proper nutritional treatment determines the effectiveness and success of therapy in these patients. Given the importance of this issue, thanks to the collaboration of scientific societies: Polish Society of Surgical Oncology (PTChO), Polish Society of Oncology (PTO), Polish Society of Clinical Oncology (PTOK) and Polish Society for Parenteral, Enteral Nutrition and Metabolism (POLSPEN) standards for nutritional therapy in oncology have been set. An introduction to nutritional therapy is the correct identification of malnourished patients. In Poland, hospitalized patients are subject to screening towards malnutrition. Nutrition intervention should be tailored to the clinical situation. It involves the use of dietary advice, use of oral diet products (oral nutritional support), enteral or parenteral nutrition, in hospital or in home, in consideration of special situations.
[Show abstract][Hide abstract] ABSTRACT: The humanized KS-interleukin-2, tucotuzumab (huKS-IL2; EMD 273066), is an EpCAM-specific immunocytokine with reported immunologic activity in combination with cyclophosphamide. This Phase 2, randomized, open-label study compared tucotuzumab/cyclophosphamide, administered as maintenance, with best supportive care (BSC) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to first-line platinum-based chemotherapy with/without prophylactic cranial irradiation (PCI). Patients received cyclophosphamide (300 mg/m, Day 1 of every 3-week cycle), followed by tucotuzumab (1.5 mg/m, Days 2-4) until disease progression. The primary endpoint was 6-month progression-free survival (PFS); the secondary objectives included overall survival (OS), treatment response, and safety. The 6-month PFS rate was lower in the tucotuzumab/cyclophosphamide group (n=64) than in the BSC group (n=44): 6.4 versus 12.2% [hazard ratio (HR): 0.98; 80% confidence interval (CI): 0.74-1.31]. HRs for PFS, time to progression, and OS indicated a similar risk of disease progression and death in both groups and best overall responses were generally comparable. For patients with previous PCI (n=26), there was a nonsignificant trend toward prolonged median PFS (1.7 vs. 1.5 months; HR: 0.60; 80% CI: 0.33-1.11) and OS (21.5 vs. 14.3 months; HR: 0.58; 80% CI: 0.31-1.05) in the tucotuzumab/cyclophosphamide group. Adverse events were more frequent with tucotuzumab/cyclophosphamide (92.2%) than with BSC (47.7%). Tucotuzumab/cyclophosphamide was well tolerated in ED-SCLC patients, but did not show PFS or OS benefits compared with BSC. The observed trend toward prolonged PFS and OS in the subgroup of patients receiving previous PCI may support further confirmation in a larger population.
No preview · Article · Aug 2015 · Anti-cancer drugs
[Show abstract][Hide abstract] ABSTRACT: In NSCLC, second-line chemotherapy using pemetrexed or docetaxel has limited efficacy and should be dedicated to selected groups of patients. Pemetrexed is an antifolate compound with the ability to inhibit enzymes (TS, DHFR and GARFT) involved in pyrimidine and purine synthesis. The objective of this study was to evaluate the association between polymorphisms of TS and MHFR genes and clinical outcomes in NSCLC patients treated with pemetrexed monotherapy. DNA was isolated from peripheral blood of 72 non-squamous NSCLC patients treated with pemetrexed. Using PCR and RFLP methods, the variable number of tandem repeats (VNTR), the G > C SNP in these repeats and insertion/deletion polymorphism of TS gene as well as 677C > T SNP in MTHFR gene were analyzed and correlated with disease control rate, progression-free survival and overall survival (OS) of NSCLC patients. Carriers of 2R/3R(G), 3R(C)/3R(G), 3R(G)/3R(G) genotypes showed significantly more frequent early progression than carriers of 2R/2R, 2R/3R(C), 3R(C)/3R(C) genotypes of TS gene (p < 0.05). Among carriers of triple 28 bp tandem repeats (3R) in TS gene and C/C genotype of MTHFR gene a significantly shorter OS was observed (HR = 3.07; p = 0.003). In multivariate analysis, significantly higher risk of death was observed in carriers of both 3R/3R genotype in TS and C/C genotype in 677C > T SNP in MTHFR (HR = 3.85; p < 0.005) as well as in patients with short duration of response to first-line chemotherapy (HR = 2.09; p < 0.005). Results of our study suggested that genetic factors may have a high predictive and prognostic value (even greater than clinical factors) for patients treated with pemetrexed monotherapy.
Full-text · Article · Aug 2015 · Pathology & Oncology Research
[Show abstract][Hide abstract] ABSTRACT: Aim: CIL is a selective, competitive inhibitor of αvβ3 and αvβ5 integrins designed to attack the tumour and its microenvironment. CERTO is a multicentre, controlled, open-label phase II study (NCT00842712) for pts with histologically confirmed newly diagnosed advanced NSCLC. Methods: Pts were initially randomised 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (CTRL), or combined with CIL 2000 mg 1x/week (CIL1W) or 2x/ week (CIL2W). During the study, an amendment triggered by cetuximab data from the FLEX study led to enrolment only of pts with EGFR histoscore ≥200, and closure of CIL2W due to feasibility issues. Primary endpoint was progression-free survival (PFS; independent read); secondary endpoints included overall survival (OS), safety, and biomarker analyses. Results: Overall, 220 pts were randomised: 85 to CIL1W; 51 to CIL2W; and 84 to CTRL. Baseline characteristics were balanced. Median PFS (independent read, ITT) was 6.2 mo in CIL1W vs 5.0 mo in CTRL (HR 0.72 [95% CI, 0.49, 1.05]; p = 0.085). For pts with EGFR ≥200, median PFS was 6.8 mo in CIL1W vs 5.6 mo in CTRL (HR 0.57 [95% CI, 0.32, 0.99], p = 0.045). Investigator-read PFS was not different between CIL1W and CTRL in either population. Median OS was 13.6 vs 9.7 mo in CIL1W vs CTRL, respectively (ITT; HR 0.81 [95% CI, 0.56, 1.17]; p = 0.265); in pts with EGFR ≥200 no difference between CIL1W vs CTR for OS was found. Generally, no relevant differences between adverse events across treatment arms were reported; nausea (56%), neutropaenia (49%), and anaemia (37%) were the most frequent, and there was no increased incidence of thromboembolic events or haemorrhages in CIL-treated pts. Biomarker sample size was small, but αvβ3 and αvβ5 expression did not reveal a prognostic correlation to PFS or OS, and was not predictive of treatment outcome. Conclusions: A benefit for addition of CIL1W to cetuximab and chemotherapy was seen for independent-read PFS, and a HR 0.81 for OS, equivalent to a 3.9 mo median survival improvement in favour of the combination, but no consistent efficacy was shown with CIL vs CTRL. The safety profile did not reveal any safety concerns for CIL.
[Show abstract][Hide abstract] ABSTRACT: The management of peritoneal surface malignancy is a significant clinical problem in oncology. It was demonstrated that the combination of complete cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may lead to long-term control of the disease or improved survival in selected patients. The aim of this paper was to present the optimal indications and technical guidelines for performing HIPEC in Poland. The application of this method requires experience of a multidisciplinary team of physicians (gynecologic oncologist, surgeon and clinical oncologist), availability of diagnostic and therapeutic resources (intensive care unit) as well as a dedicated perfusion system. A crucial aspect for obtaining optimal treatment outcomes is the selection of patients. Such a selection takes place both at the beginning of treatment and intraoperatively. The initial selection of patients qualified for HIPEC includes ruling out extraperitoneal spread of cancer and metastases to the liver (single resectable liver metastases in patients with colorectal carcinoma are not contraindications) and lungs. According to current international guidelines, the HIPEC procedure is a standard treatment in patients with ovarian carcinoma that metastasizes to the peritoneum, in colorectal cancer, when PCI <20 and in patients with peritoneal mesothelioma or pseudomyxoma peritonei as well as in patients with gastric cancer.
Full-text · Article · Aug 2014 · Current Gynecologic Oncology
[Show abstract][Hide abstract] ABSTRACT: Testing for EGFR gene mutations and ALK gene rearrangement is routinely used in advanced non-small-cell lung cancer for adequate patient selection to molecularly targeted therapies. We present Polish methodological recommendations for molecular analysis of EGFR and ALK genetic abnormalities. Recommendations specify clinical indications for testing, sample types and handling, as well as requirements for laboratories performing molecular diagnostics.
No preview · Article · Aug 2014 · Pneumonologia i alergologia polska: organ Polskiego Towarzystwa Ftyzjopneumonologicznego, Polskiego Towarzystwa Alergologicznego, i Instytutu Gruzlicy i Chorob Pluc
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients.
Patients and methods:
Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients.
Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients.
Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients.
Full-text · Article · Aug 2014 · Clinical Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Testing for the epidermal growth factor receptor (EGFR) gene mutations requires considerable multidisciplinary experience of clinicians (for appropriate patient selection), pathologists (for selection of appropriate cytological or histological material) and geneticists (for performing and reporting reliable molecular tests). We present our experience on the efficacy of routine EGFR testing in various types of tumor samples and the frequency of EGFR mutations in a large series of Polish non-small cell lung cancer (NSCLC) patients.
Deletions in exon 19 and substitution L858R in exon 21 of EGFR gene were assessed using real-time PCR techniques in 1,138 small biopsies or cytological specimens and in 1,312 surgical samples.
Out of 2,450 diagnostic samples (containing >10% of tumor cells), the occurrence of EGFR gene mutations was 9%; more frequently in women (13.9%) and adenocarcinoma patients (10%), particularly with accompanying expression of TTF1 (13.0%). The frequency of EGFR gene mutations was similar in cytological and histological specimens, and in primary and metastatic lesions, and did not depend on the percentage of tumor cells and quality of isolated DNA. Cytological or small biopsy, compared to surgical specimens showed lower percentage of tumor cells, with no impact on the quality of real-time PCR assay.
Cytological and small biopsy samples with low (10-20%) content of tumor cells and specimens from metastatic lesions are a sufficient source for EGFR mutation testing in NSCLC patients. The incidence of EGFR gene mutations in examined population was similar to those reported in other Caucasian populations.
Full-text · Article · Aug 2014 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: We presented retrospective analysis of up to five polymorphisms in TS, MTHFR and ERCC1 genes as molecular predictive markers for homogeneous Caucasian, non-squamous NSCLC patients treated with pemetrexed and platinum front-line chemotherapy.
The following polymorphisms in DNA isolated from 115 patients were analyzed: various number of 28-bp tandem repeats in 5'-UTR region of TS gene, single nucleotide polymorphism (SNP) within the second tandem repeat of TS gene (G>C); 6-bp deletion in 3'-UTR region of the TS (1494del6); 677C>T SNP in MTHFR; 19007C>T SNP in ERCC1. Molecular examinations' results were correlated with disease control rate, progression-free survival (PFS) and overall survival.
Polymorphic tandem repeat sequence (2R, 3R) in the enhancer region of TS gene and G>C SNP within the second repeat of 3R allele seem to be important for the effectiveness of platinum and pemetrexed in first-line chemotherapy. The insignificant shortening of PFS in 3R/3R homozygotes as compared to 2R/2R and 2R/3R genotypes were observed, while it was significantly shorter in patients carrying synchronous 3R allele and G nucleotide. The combined analysis of TS VNTR and MTHFR 677C>T SNP revealed shortening of PFS in synchronous carriers of 3R allele in TS and two C alleles in MTHFR. The strongest factors increased the risk of progression were poor PS, weight loss, anemia and synchronous presence of 3R allele and G nucleotide in the second repeat of 3R allele in TS. Moreover, lack of application of second-line chemotherapy, weight loss and poor performance status and above-mentioned genotype of TS gene increased risk of early mortality.
The examined polymorphisms should be accounted as molecular predictor factors for pemetrexed- and platinum-based front-line chemotherapy in non-squamous NSCLC patients.
Full-text · Article · Jul 2014 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Introduction
A dose-determination study was conducted in untreated stage III NSCLC to assess continuous exposure to fractionated oral vinorelbine (NVBo), a radiosensitizer, during the radiotherapy period, either alone (1st cohort) or in combination with cisplatin (2nd cohort).
Three patients stage IIIAN2/IIIB NSCLC were expected at each dose-level with 3 additional patients in case of dose-limiting toxicity (DLT). Concomitantly with 60Gy total dose radiotherapy, NVBo was given from 60mg up to 180mg total-dose/week split on days 1, 3 and 5. Once the maximal tolerated dose (MTD) defined as 2 DLT in a dose-level was determined and the recommended dose of NVBo alone established, the trial assessed its recommended dose in combination with cisplatin 80mg/m2 every 3 weeks.
In the 1st cohort, 26 patients were enrolled. MTD was 160mg/week: 3 Grade (G) 3 oesophagitis and 1 G3 pneumonia as DLT out of 5 patients in this dose-level. In the recommended dose-level (150mg/week), only 1/6 patients experienced a DLT. In the 2nd cohort, 11 patients received NVBo weekly doses from 130mg to 150mg with cisplatin. Only 2 patients received 150mg/week NVBo, the trial closed before MTD was determined. Confirmed response rate was 42% and 55% in the 1st and 2nd cohort, respectively.
The recommended dose of this fractionated NVBo scheme as single agent concomitantly with radiotherapy for 6 weeks is 50mg day 1, 3, 5 (150mg/week); combined with cisplatin 80mg/m2 every 3 weeks, the dose should be 140-150mg/week adapted on hematology. The response rate is promising.
No preview · Article · Jul 2014 · Clinical Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Oral vinorelbine plus cisplatin has been studied in numerous trials as first-line treatment of patients with Non-Small Cell Lung Cancer (NSCLC) regardless of histological subtype. NAVoTrial 01 is the first study that explores this combination specifically in Non-Squamous (NS) NSCLC by assessing the feasibility of this doublet in an investigational approach (ratio 1:2). A reference arm with pemetrexed plus cisplatin was included. Maintenance therapy with single agent after four cycles of combination was included in the study schedules as it reflected a trend in first-line treatment of NSCLC.
Stage IIIB/IV untreated/relapsed NS NSCLC patients received in a 3-week cycle pemetrexed 500 mg/m², and cisplatin 75 mg/m² day 1 (Arm A) or oral vinorelbine 80 mg/m² days 1, 8 (first cycle 60 mg/m²), cisplatin 80 mg/m² day 1 (Arm B). After 4 cycles, patients without progression received single agent maintenance with pemetrexed or oral vinorelbine.
Overall, 153 patients were randomized (ArmA/ArmB): 51/102. Disease Control Rate (%) was 76.5 (95% CI, 62.5-87.2)/75.0 (95% CI, 65.3-83.1), Response Rates (%) 31.4 (95% CI, 19.1-45.9)/24.0 (95% CI, 16.0-33.6), median progression-free survival (months) 4.3 (95% CI, 3.8-5.6)/4.2 (95% CI, 3.6-4.7), median survival (months) 10.8 (95% CI, 7.0-16.4)/10.2 (95% CI, 7.8-11.9). Main grade 3/4 hematological toxicities (%) were neutropenia 18.3/44.0, whereas febrile neutropenia was reported in 2% of patients in each arm.
Oral vinorelbine and cisplatin reported an efficacy in line with that achieved with a standard treatment as pemetrexed and cisplatin, coupled with an acceptable safety profile.
Full-text · Article · Jul 2014 · Clinical Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Recent oncology development results in significant reduction of morbidity and mortality of several kinds of cancer. Such great achievements are at the cost of frequent cardiotoxicity, which predominantly is manifested as cardiomyopathy, cardiac dysfunction and heart failure (HF). Cardiotoxicity may manifest early - during treatment or late - after treatment completion. There are type 1 - anthracycline-related and type 2 - trastuzumab-related cardiotoxicity. Early detection of cardiotoxicity is crucial for preventing late heart dysfunction and HF. Baseline echocardiographic assessment should be performed in every patient before initiation of cancer treatment and serial monitoring of cardiac safety by means of echocardiography is recommended. The most widely used for this purpose is left ventricular ejection fraction (LVEF) calculated by Simpson's method with2 dimensional transthoracic echocardiography. LVEF has numerous limitations, among which significant inter- and intraobserver variability, late decrease of LVEF with its often irreversibility are the most important. Noncontrast 3 dimesional echocardiography is the most reproducible technique for LVEF measurement. Newer echocardiographic technique - myocardial strain imaging has the potential to detect early subclinical cardiac dysfunction due to cardiotoxicity and may be used for the prediction of LV dysfunction. The role of other echocardiographic parameters, particularly of LV diastolic function has not been exactly defined in literature. The decision on discontinuation or modification of cancer therapy should be based on 2 improper, separate measurements of particular echocardiographic parameter or better more than 1 improper parameter should be taken into account. After completion of cancer treatment, echocardiography follow-up is recommended to detect late cardiotoxicity.
No preview · Article · Jun 2014 · Kardiologia polska
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Figitumumab (CP-751,871), a fully human immunoglobulin G2 monoclonal antibody, inhibits the insulin-like growth factor 1 receptor (IGF-1R). Our multicenter, randomized, phase III study compared figitumumab plus chemotherapy with chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC).
Patients and methods:
Patients with stage IIIB/IV or recurrent NSCLC disease with nonadenocarcinoma histology received open-label figitumumab (20 mg/kg) plus paclitaxel (200 mg/m(2)) and carboplatin (area under the concentration-time curve, 6 mg · min/mL) or paclitaxel and carboplatin alone once every 3 weeks for up to six cycles. The primary end point was overall survival (OS).
Of 681 randomly assigned patients, 671 received treatment. The study was closed early by an independent Data Safety Monitoring Committee because of futility and an increased incidence of serious adverse events (SAEs) and treatment-related deaths with figitumumab. Median OS was 8.6 months for figitumumab plus chemotherapy and 9.8 months for chemotherapy alone (hazard ratio [HR], 1.18; 95% CI, 0.99 to 1.40; P = .06); median progression-free survival was 4.7 months (95% CI, 4.2 to 5.4) and 4.6 months (95% CI, 4.2 to 5.4), respectively (HR, 1.10; P = .27); the objective response rates were 33% and 35%, respectively. The respective rates of all-causality SAEs were 66% and 51%; P < .01). Treatment-related grade 5 adverse events were also more common with figitumumab (5% v 1%; P < .01).
Adding figitumumab to standard chemotherapy failed to increase OS in patients with advanced nonadenocarcinoma NSCLC. Further clinical development of figitumumab is not being pursued.
Full-text · Article · Jun 2014 · Journal of Clinical Oncology