Eleonora Bona

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

Discordant somatic and germline VEGF-A genotype in a cancer patient resistant to paclitaxel/bevacizumab with chemosensitive hepatic metastasis

Recent data reported an association between VEGF-A genotype of tumors and median overall survival as well as grade 3 or 4 hypertension when using bevacizumab in metastatic breast cancer. In the present case we report a discordant VEGF-A genotype between tumor and normal tissue in a patient with a responsive hepatic lesion of chemoresistant breast cancer treated with bevacizumab and paclitaxel. Moreover, we show that, despite the very low VEGF-A protein expression, the neoplastic lesion was well vascularized and responded to bevacizumab therapy. The discordance of VEGF-A polymorphisms in tumor and germline DNA may suggest the importance of obtaining both information in order to predict a superior overall survival or a lower risk of hypertension in patients treated with taxanes and bevacizumab.

Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab

AIM To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. PATIENTS & METHODS Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. RESULTS One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4-16.8) and 10.2 months (95% CI: 8.8-11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29-0.66, p < 0.0001). CONCLUSION The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome.

Cardiac safety of adjuvant non-pegylated liposomal doxorubicin combined with cyclophosphamide and followed by paclitaxel in older breast cancer patients

PURPOSE To investigate the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) combined to Cyclophosphamide (CTX) and followed by weekly Paclitaxel, in older patients (≥65 years) with diagnosis of high risk breast cancer. The main end point of this prospective study was the detection of early episodes of symptomatic congestive heart failure (CHF). METHODS The cardiac function was evaluated by left ventricular ejection fraction (LVEF) measurements with repeated echocardiograms, performed 2 weeks before the beginning of chemotherapy and every 6 months, until 30 months after the study entry; then yearly for at least 5 years. RESULTS Forty-seven patients were enrolled from two Italian Divisions of Medical Oncology. Final results revealed no early episodes of symptomatic CHF within the first 12 months from the enrolment. Only two cardiac events were observed: an episode of atrial flutter after the first cycle of NPL-DOX and CTX, with a quick return to normal rhythm, and a grade 3 (scored to NCI-CTCAE, version 3.0) CHF episode, 18 months later chemotherapy start. No other relevant toxicities were reported. CONCLUSIONS This adjuvant combination including NPL-DOX in elderly patients, resulted in a low rate of cardiac toxic effects. Comparative trials should be encouraged to confirm these findings.

Strategie di prevenzione e cura in oncologia: differenze di genere

Gender difference in cancer susceptibility, incidence, prognosis and aggressiveness have been observed for several types of tumors. Environmental and occupational exposures along with hormonal and immunological differences may be responsible for the disparity between males and females. Tumor immune surveillance, a recognized major physiological mechanism against cancer development and progression, is largely sex-dependent with a great activity in females respect to males. However, up today, no clinical trial evaluating new drugs or treatment strategy have been performed in a gender-specific manner and our knowledge derived from subgroup analysis, especially for what concerns women population. In this review, the authors point out gender differences in cancer epidemiology, response to treatments, toxicity and tumors related side effects. Colorectal and lung cancers will also described in order to underline the main gender differences.

Abstract P1-08-31: Putative role of genetic variants of eNOS in survival and toxicity of patients given antiangiogenic therapy

Background: The development of tumor angiogensis is mainly driven by vascular endothelial growth factor (VEGF), which is strongly overexpressed in many cancers. VEGF induces the expression of the endothelial nitric oxide (NO) synthase (eNOS) and the resultant overproduction of NO may be associated with recruitment of inflammatory cells, disruption of endothelial barrier, edema and impaired drug delivery within tumors (1). Functional polymorphisms in the eNOS gene, including -786C>T and 894G>T, have been associated with impaired production of NO and higher incidence of hypertension (HT) (2), diabetic nephropathy (3) and glaucoma (4). Since suppression of VEGF-eNOS signal transduction by antiangiogenic drugs may normalize tumor vasculature by restoring interstitial fluid pressure and drug distribution in tumors, but may induce HT in patients, the purpose of this study was to examine the association between the major eNOS variants -786C>T and 894G>T with treatment outcome and risk of HT in metastatic breast cancer (MBC) patients given bevacizumab. Methods: Sixty-five MBC patients given bevacizumab as per approved indication were enrolled. Main characteristics were: mean age 49.5 years (range 29-73) at first diagnosis, 53 years (range 34-74) at metastatic progression and PS 0-1. Four subjects with HT and 1 patient with compensated cardiovascular disease were also included. First-line chemotherapy for metastatic disease was taxol plus bevacizumab. Germline DNA was extracted from peripheral blood with the Qiamp Mini Kit (Qiagen, Milano, Italy) and examined for eNOS -786C>T and 894G>T variants by Real Time PCR (Life Sciences 7900HT platform) and automatic sequencing (Life Sciences 3100 Avant). The study was approved by the local Ethics Committee. Results: Genotype frequencies are reported below (Table 1). The presence of -786TT genotype was associated with longer PFS compared with the other genotypes (median PFS 95%CI, CC/CT = 9 vs TT = 12 months, Log-rank [Mantel Cox] test p = 0.0066), but not with any grade of HT. Also the 894GT/TT was associated with longer PFS compaed with the GG homozygous wild-type genotype (median PFS 95%CI, GG = 7,5 vs GT/TT = 10 months, Log-rank [Mantel-Cox] test p = 0,0497). The incidence and severity of HT did not vary among genotypes. Conclusion: Patients bearing deficient eNOS variant did not experience higher risk or severity of HT with respect to the wild-type allele but enjoied a longer PFS. View this table: Table 1. Genotype frequencies References 1. Goel S et al. Physiol Rev 2011;91:1071 2. Niu W, Qi Y. PLoS One 2011;6:e24266 3. Rahimi Z et al. Dis Markers 2013;34:437 4. Awadalla MS et al. Invest Ophtalmol Vis Sci 2013;54:2108. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-31.

Abstract P5-17-06: The deficient eNOS c.894G>T genotype is not associated with increased severity of hypertension and proteinuria in breast cancer patients receiving bevacizumab

Background. Tumor angiogenesis is a complex process involving a wide array of effector molecules and stromal cells. In tumor tissue, vasculature is structurally and functionally abnormal, causing elevated interstitial pressure and irregular perfusion. The expression of vascular endothelial growth factor (VEGF), the most important angiogenic factor, is enhanced in many tumors. VEGF may induce nitric oxide (NO) production via up-regulation of the endothelial NO synthase (eNOS, NOS3) and the resultant overproduction of NO is associated with vasodilation and edema within tumors (Goel S et al. Physiol Rev 2011;91:1071). eNOS plays an important physiologic role in maintaining blood pressure homeostasis and vascular integrity by providing constitutive release of NO in endothelial cells. Functional variants of the eNOS gene, including the single-nucleotide polymorphism rs1799983 (c.894G>T, p. Asp298Glu) at codon 298, have been associated with reduced function of eNOS and higher incidence of hypertension (HT) (Niu W, Qi Y. PLoS One 2011;6:e24266). Purpose. Since suppression of VEGF-eNOS axis by anti-angiogenic therapies is considered a causative factor of HT in patients, the purpose of this study was to examine whether the major eNOS non-synonymous variant c.894G>T may be associated with increased risk of developing hypertension (HT) and proteinuria (PU) in breast cancer patients treated with bevacizumab. Patients and methods. Forty-one metastatic breast cancer patients given bevacizumab as per standard of care were enrolled. Main characteristics were: median age 49.5 years (range 29–73) at first diagnosis, 53 years (range 34–74) at metastatic disease; PS 0–1 in all patients; 4 subjects with hypertension and 1 patient with compensated cardiovascular disease at diagnosis. Twenty-six subjects had received neoadjuvant or adjuvant chemotherapy based on anthracycline and taxane; first-line chemotherapy for metastatic disease was paclitaxel plus bevacizumab for all patients; 14 subjects received hormone-therapy for metastatic disease (range 1–5 lines). Germline DNA was extracted from peripheral blood and used to screen patients for eNOS c.894G>T variant by automatic sequencing. The study was approved by the local Ethics Committee. Results. Three patients (7.3%) were homozygous variant c.894TT, 12 (29.3%) homozygous wild-type c.894GG and the remaining 26 (63.4%) were heterozygous c.894GT. The c.894TT patients had no HT or PU at baseline and developed grade (G) 1, 2, 2 HT, respectively, and in one case PU during treatment. G1, 2 and 3 HT developed in 4, 5 and 2 c.894GG subjects, respectively, while PU was observed in 7/12 (58%) patients. The full range of HT grades and PU were observed in heterozygous subjects. Thirty-seven patients achieved one of the following: partial remission, minimal response or stable disease upon treatment with bevacizumab in combination with chemotherapy; 3 subjects had progressive disease and 1 was not evaluable. Conclusions. The presence of the mutant T allele of c.894G>T is not associated with increased severity of HT and PU; therefore, bevacizumab can be administered at no increased risk in TT patients with respect to the wild-type GG population. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-06.