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Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer

PURPOSEnRegulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.nnnPATIENTS AND METHODSnPatients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)(n) dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.nnnRESULTSnIn 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (chi(2) test = 12.7; P = .001) and treatment response (chi(2) test = 9.45; P = .008) than EGFR intron-1 L/L carriers.nnnCONCLUSIONnAlthough additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3′-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56–5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III–IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer

Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients. Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done. Results: A confirmed prostate-specific antigen decrease of ≥50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones. Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.

Prolonged fixed dose rate infusion of gemcitabine with autologous haemopoietic support in advanced pancreatic adenocarcinoma.

This study aimed to define the maximum-tolerated dose (MTD) of fixed dose rate (FDR) of gemcitabine (2′-2′-difluorodeoxycitidine) infusion with circulating haemopoietic progenitor support and to evaluate the activity of the treatment. Secondary end points were pharmacokinetic of gemcitabine and difluorodeoxyuridina (dFdU) measured at first course and the activity andexpression profile of cytidine deaminase (CdA) on circulating mononuclear cells. Patients with advanced pancreatic carcinoma received escalating dose of gemcitabine 10u2009mgu2009m−2u2009min−1 every 2 weeks with circulating haemopoietic progenitor support. First dose level was 3000u2009mgu2009m−2 and the doses were increased by 500u2009mgu2009m−2 until MTD. In all, 23 patients were enrolled. Toxicities were mild or moderate; the only patient treated at 7000u2009mgu2009m−2 died because of toxicity; therefore; the MTD was established at 6500u2009mgu2009m−2. The overall response rate was 22.2%. The AUC of gemcitabine showed a dose-dependent increase, while the AUC of dFdU reached a plateau at 4500u2009mgu2009m−2. A significant relationship was found between the AUC of dFdU and CdA expression and activity (P<0.05). Moreover, progression rate and survival were significantly related to CdA expression and activity levels. The activity of high-dose gemcitabine is not superior to that reported with less intensive FDR schedules. The predictive role of CdA expression and activity on outcome deserves further investigation.

Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers

AimsTo evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.MethodsThirty-eight patients received 500xa0mg/mq2 CTX i.v bolus on day 1 and, from day 2, 50xa0mg/day CTX p.o. plus 100xa0mg/twice a day UFT p.o. and 200xa0mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH2, GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed.ResultsSeventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8xa0ms (range, 4.2–7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7xa0ms (95% CI, 1.6–3.9xa0ms) and 7.1xa0ms (95% CI, 4.3–9.9xa0ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and Cmax values greater than 1.313xa0hxa0×xa0μg/ml and 0.501xa0μg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients.ConclusionMetronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.

Background:No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone.Methods:Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (−2578A/C, −634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy–Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher’s exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan–Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant.Results:Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the −2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the −634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the −634CC genotype had a median PFS of 2.2 months whereas patients with the genotype −634CG/GG had a median PFS of 6.25 months (P=0.0042).Conclusion:The −634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.

METRONOMIC CYCLOPHOSPHAMIDE IN ELDERLY PATIENTS WITH ADVANCED, CASTRATION‐RESISTANT PROSTATE CANCER

To the Editor: Metronomic chemotherapyFlow-dose, long-term, frequently administered chemotherapyFhas been found to have an important effect on the stabilization of cancer, including prostate cancer, without any highgrade toxicity. However, no data from prospective metronomic clinical trials are available in elderly patients with cancer. Anecdotal case reports and a small retrospective clinical study on metastatic melanoma have suggested metronomic chemotherapy as an alternative therapy in elderly patients requiring palliation. The present study was a retrospective review of 29 consecutive elderly patients (aged 78) with advanced castration-resistant prostate cancer (CRPC) who had been treated with metronomic cyclophosphamide (50 mg per day by mouth) plus celecoxib (200 mg twice a day by mouth) and dexamethasone (1 mg once daily by mouth) at Pisa University Hospital and Livorno General Hospital. The treatment was given for at least 12 weeks. Median age was 83 (range 78–92); six patients (20%) had an Eastern Cooperative Oncology Group Performance Status (PS) of 0 and 23 (80%) of 1 or more; the median number of comorbidities was 2 (range 0–6), and 19 patients (65%) were deemed frail. Median baseline serum prostate specific antigen (PSA) level was 49.4 ng/mL (range 6.7– 567.8 ng/mL); bone was the most frequent metastatic site (72.4%); two patients had measurable disease (7%). Ten patients (34.5%) received one or more previous chemotherapeutic lines, including docetaxel (9 patients, 31%), mitoxantrone (5 patients, 10%), estramustine phosphate (7 patients, 24%), and vinorelbine and etoposide (1 patient, 3.4%). Zoledronic acid was administered to 19 patients (65.5%). No Grade 3 or 4 hematological or nonhematological toxicities were observed in the 29 assessable patients. Four patients (14%) developed National Cancer InstituteF Common Toxicity Criteria Grade 2 anemia, and two patients (7%) developed Grade 2 thrombocytopenia (one of these patients required cyclophosphamide discontinuation). Neither major cardiovascular events nor toxicity-related deaths were observed. Overall, 18 patients (62%) experienced any reduction in PSA level (a decrease of 2% to 99%); 13 (45%) had a confirmed PSA decrease of 50% or greater. Of the 13 responders (77%), 10 had not received any prior chemotherapy, whereas the remaining three had previously received chemotherapy (median 2 lines of chemotherapy). Moreover, nine of the 16 nonresponders had previously been received chemotherapy, and seven had not. Based on these results, there was not any statistical difference in the clinical activity in this metronomic combination between patients previously treated or untreated (P 5.43; Fisher exact test). One of two patients (7%) with measurable disease according to the Response Evaluation Criteria In Solid Tumors obtained a partial response, and the other showed disease stabilization. Median duration of response of the 18 patients with any reduction in PSA levels was 8.6 months (95% confidence interval (CI) 5 7.6–9.6 months). After a median follow-up of 27.3 months (95% CI 5 18.8–35.8 months), median progression-free survival and median overall survival were 7.7 months (95% CI 5 2.3–13.1 months) and 19.7 months (95% CI 5 12.8– 26.6 months), respectively (Figure 1). Palliative docetaxel plus low-dose prednisone every 3 weeks is the standard treatment for CRPC. The clinical efficacy and tolerability of first-line docetaxel was recently reported on in 175 patients aged 75 and older. The authors observed a favorable safety and efficacy profile of 3 weeks of docetaxel only in ‘‘fit’’ elderly patients with prostate cancer (PS 1). Conversely, 46% of patients received an adapted docetaxel regimen (delivered on a weekly schedule in nearly 90% of the cases) because of their vulnerable condition: aged 80 and older or a PS of 2 or greater. However, this subgroup of patients also experienced severe nonhematological toxicity in approximately 40% of the cases. Such results lead the authors to consider the weekly regimen less safe than reported previously in elderly patients with prostate cancer. Despite the known limitations of a retrospective study with a small sample size, the regimen in the current study was feasible and demonstrated a favorable toxicity profile even in elderly and ‘‘unfit’’ patients with prostate cancer. A good toxicity profile was also seen in patients treated for longer

Current challenges in HER2-positive breast cancer.

The introduction of trastuzumab into routine clinical practice has had a dramatic effect on the outlook for patients with HER2-positive breast cancer. Nevertheless, answers to some long unresolved questions about the optimal use of trastuzumab (such as its role in small tumors or low-risk disease, cardiac safety in the elderly, and treatment duration) have emerged only relatively recently. Moreover, with the availability of new highly effective HER2-directed therapies, including pertuzumab and trastuzumab-emtansine (T-DM1), the treatment algorithm for HER2-positive breast cancer continues to evolve. This review provides a summary of the latest evidence providing insight into the management of early and advanced HER2-positive breast cancer and delineates future perspectives of study and treatment for these patients.

Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7–43.7 months) and 28.6 months (95% confidence interval: 25.6–30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers’ status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90–100 and 70–80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.

Metronomic chemotherapy for metastatic prostate cancer: a 'young' concept for old patients?

Prostate cancer is a common disease in the elderly, and the number of older prostate cancer patients will probably increase with both the aging of the population and the increased rate of screening. In elderly patients with several co-morbidities, cancer management can be complex, and the risk of administering toxic therapy in this setting should be carefully evaluated. Metronomic chemotherapy, i.e. low-dose, long-term, frequently administered chemotherapy, has been shown to have a significant stabilizing effect on cancer and a positive impact on the quality of life of patients, including those with prostate cancer. Given the low toxicity profile of metronomic chemotherapy, elderly patients or patients with co-morbidities may be candidates for a first-line or second-line oral metronomic approach when standard chemotherapies are contraindicated or not acceptable to the patient. Moreover, the possibility of patients being able to spend more time at home is an important component of a palliative treatment such as metronomic chemotherapy. Unfortunately, and despite these considerations, very few data are available on the activity and safety of metronomic chemotherapy in elderly patients. However, retrospective analyses conducted in a small cohort of patients have been published and, notwithstanding their limitations, indicate that novel metronomic schedules are well tolerated, safe and show potentially interesting activity in elderly, ‘unfit’ (poor performance status) patients with metastatic prostate cancer. Therefore, evaluation of metronomic chemotherapy strategies in prospective, randomized, phase II/III clinical studies of elderly patients with metastatic prostate cancer appears to be warranted.