Felipe Melo Cruz

Phase III, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel (TAK-700) Plus Prednisone With Placebo Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer That Has Progressed During or After Docetaxel-Based Therapy: ELM-PC 5

PURPOSE Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. PATIENTS AND METHODS In our study, 1,099 men were randomly assigned in a 2:1 schedule to receive orteronel 400 mg plus prednisone 5 mg twice daily or placebo plus prednisone 5 mg twice daily, stratified by region (Europe, North America [NA], and non-Europe/NA) and Brief Pain Inventory-Short Form worst pain score. Primary end point was overall survival (OS). Key secondary end points (radiographic progression-free survival [rPFS], ≥ 50% decrease of prostate-specific antigen [PSA50], and pain response at 12 weeks) were to undergo statistical testing only if the primary end point analysis was significant. RESULTS The study was unblinded after crossing a prespecified OS futility boundary. The median OS was 17.0 months versus 15.2 months with orteronel-prednisone versus placebo-prednisone (hazard ratio [HR], 0.886; 95% CI, 0.739 to 1.062; P = .190). Improved rPFS was observed with orteronel-prednisone (median, 8.3 v 5.7 months; HR, 0.760; 95% CI, 0.653 to 0.885; P < .001). Orteronel-prednisone showed advantages over placebo-prednisone in PSA50 rate (25% v 10%, P < .001) and time to PSA progression (median, 5.5 v 2.9 months, P < .001) but not pain response rate (12% v 9%; P = .128). Adverse events (all grades) were generally more frequent with orteronel-prednisone, including nausea (42% v 26%), vomiting (36% v 17%), fatigue (29% v 23%), and increased amylase (14% v 2%). CONCLUSION Our study did not meet the primary end point of OS. Longer rPFS and a higher PSA50 rate with orteronel-prednisone indicate antitumor activity.

Gabapentin for the prevention of chemotherapy- induced nausea and vomiting: a pilot study

INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) is a distressing side effect that affects many patients undergoing emetogenic chemotherapy, despite the use of antiemetic medications. The purpose of this trial was to evaluate the efficacy and safety of gabapentin for the prevention of CINV during the first cycle of treatment in patients receiving moderately or highly emetogenic chemotherapy. METHODS Eighty chemotherapy-naive patients, scheduled to receive moderately and highly emetogenic chemotherapy, were enrolled in this randomised, double-blind, placebo-controlled clinical trial. All patients received intravenous ondansetron 8 mg, dexamethasone 10 mg and ranitidine 50 mg before chemotherapy on day 1 and oral dexamethasone 4 mg twice a day on days 2 and 3. Patients were randomly assigned to take gabapentin 300 mg or placebo on the following schedule: 5 and 4 days before chemotherapy once daily, 3 and 2 days before chemotherapy twice daily, 1 day before to 5 days after chemotherapy thrice daily. The primary endpoint was complete overall protection from both vomiting and nausea over the course of the entire study (day 1 through day 5), and complete protection during the delayed period (24-120 h after chemotherapy). RESULTS The proportion of patients achieving complete response improved from 40% to 62.5%, (p = 0.04) when comparing the control group and the gabapentin group, respectively. In the subset of patients who achieved complete control in the acute phase, the percentage of patients who achieved delayed complete control was higher in the gabapentin group (89.3 × 60.7%, p = 0.01). Adverse events did not significantly differ between study arms. CONCLUSIONS Gabapentin is a low-cost strategy to improve complete control of CINV, specially delayed CINV control.

Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: a pilot randomized clinical trial

CONTEXT AND OBJECTIVE Oxaliplatin is one of the chemotherapy regimens most used for treating colorectal cancer. One of the main limitations to its use is induction of peripheral neuropathy. Previous studies have shown that vitamin E can reduce the incidence of peripheral neuropathy by 50%. This study aimed to assess the effectiveness of vitamin E for prevention of oxaliplatin-induced peripheral neuropathy. DESIGN AND SETTING Prospective, phase II, randomized pilot study developed at a university hospital in the Greater ABC region. METHODS Patients were randomized five days before starting oxaliplatin treatment, to receive either vitamin E or placebo until the end of the chemotherapy regimen. The outcome was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3, and specific gradation scales for oxaliplatin-induced peripheral neuropathy. Patients with colorectal and gastric cancer who had been scheduled to receive oxaliplatin-based chemotherapy were included. Both groups received calcium and magnesium supplementation before and after oxaliplatin infusions. RESULTS Eighteen patients were randomized to the vitamin E group and 16 to the placebo group. Cumulative incidence of 83% with peripheral neuropathy grades 1/2 was observed in the vitamin E group, versus 68% in the placebo group (P = 0.45). A trend towards more diarrhea was observed among patients who received vitamin E (55.6% vs. 18.8%; P = 0.06). There were no other significant differences in toxicity between the groups. CONCLUSIONS No significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy was demonstrated through vitamin E use. CLINICAL TRIAL REGISTRATION NCT01523574.

Biomarkers of fatigue related to adjuvant chemotherapy for breast cancer: evaluation of plasma and lymphocyte expression

BackgroundFatigue is common in cancer patients receiving adjuvant chemotherapy. To further understand the mechanism of fatigue and search for potential biomarkers, we conducted this prospective study. MethodsWe enrolled breast cancer (BC) patients before their first adjuvant Adriamycin-based chemotherapy cycle. Patients responded to the brief fatigue inventory (BFI) and Chalder fatigue questionnaires and had their blood drawn for both plasma evaluation and evaluation of the peripheral mononuclear cell fraction (PMNCF) mRNA expression of various biomarkers. We evaluated FSH, LH, estradiol, DHEA, DHEAS, IL6, IL2, ILIRA, IL1β, CRP, Cortisol in the plasma and IL2, IL10, IL6, TGF-β, KLRC1, TNF, BTP, SNCA, SOD1, BLNK, PTGS2 and INF γ expression in the PMNCF.Results11 patients did not exhibit an increase in their BFI scores and served as controls, whereas 32 patients exhibited an increase in their BFI scores compared with the baseline scores. From the biomarkers we evaluated in the PMNCF, the only one significantly associated with fatigue was TGF-β (p = 0.0343), while there was a trend towards significance with KLRC1 (p = 0.0627). We observed no evidence of significant associations of any plasma biomarkers with the development of fatigue. However when we analyzed patients with more severe fatigue, plasma IL1-RA levels correlated directly with higher fatigue scores (p = 0.0136).ConclusionsWe conclude that fatigue induced by chemotherapy in BC patients is associated with changes in IL1-ra plasma levels and in TGF-β lymphocyte expression. Its mechanism may be different than that observed in long-term BC survivors or that induced by radiation therapy.Trial registrationNCT02041364 [ClinicalTrials.gov]

Purified dry extract of Paullinia cupana (guaraná) (PC-18) for chemotherapy-related fatigue in patients with solid tumors: An early discontinuation study

ABSTRACT Purpose: Paullinia cupana (guaraná) is an Amazonian plant that has been previously shown to be effective in treating chemotherapy-related fatigue (CRF) in patients with breast cancer. We aimed to evaluate the efficacy of a purified dry extract of P. cupana (PC-18) in patients with various solid tumors treated with chemotherapy. Methods: We included 40 patients with solid tumors who showed increases in their Brief Fatigue Inventory (BFI) questionnaire scores after 1 week of systemic chemotherapy. PC-18 was administered at 37.5 mg by mouth two times per day (PO bid), starting after 1 week of chemotherapy, for 3 weeks (induction phase). Patients who had an improvement in or stabilization of their BFI scores were randomized to receive either PC-18 at the same dose or placebo for the following 3 weeks (maintenance phase). Results: After PC-18 treatment, the BFI fatigue scores improved or stabilized in 36 out of the 40 patients (mean BFI score difference = 2.503; 95% confidence interval: 1.716–3.375, p = .0002). Three weeks after randomization (16 patients on PC-18 and 17 on placebo), we observed no significant differences in the BFI, Functional Assessment of Chronic Illness Therapy, Hospital Anxiety and Depression Scale, and Pittsburgh Sleep Quality Index scores between patients randomized to PC-18 versus placebo. Conclusions: We conclude that the PC-18 extract may be effective for the treatment of CRF in patients with a variety of solid tumors. A conditioning effect, which was observed in patients who had a beneficial effect of PC-18 on CRF, may explain the better than expected fatigue scores of the placebo-treated patients.

Involvement of signaling molecules in the prediction of response to imatinib treatment in metastatic GIST patients.

Imatinib therapy has undoubtedly contributed to the treatment of metastatic gastrointestinal stromal (GIST) tumors that were previously untreatable. However, disease progression during treatment with tyrosine kinase inhibitors remains an issue in clinical practice not fully explained by KIT and PDGFRA mutation status. We investigated the role of three important signaling molecules (insulin-like growth factor 1 receptor [IGF1R], protein kinase C-θ [PKCθ], and Raf kinase inhibitor protein [RKIP]) that have been implicated in GIST pathogenesis as potential biomarkers for prediction of response to imatinib treatment. We retrospectively reviewed 76 patients with metastatic GIST submitted to imatinib treatment between 2002 and 2007, and analyzed 63 of them. Insulin-like growth factor 1, total PKCθ, phosphorylated PKCθ, and RKIP immunohistochemical expression were correlated with objective response to imatinib treatment and progression-free and overall survival. Median follow-up was 31.2 mo (95% confidence interval, 26.3-36.1 mo). There was a statistically significant association between IGF1R expression and type of response to imatinib treatment (P = 0.05)-that is, higher IGF1R expression was related to lower objective response. However, IGF1R higher expression did not affect progression-free and overall survival. Insulin-like growth factor 1, but not PKCθ and RKIP, emerges as a potential biomarker for prediction of response to imatinib treatment in metastatic GISTs. Validation studies are warranted.

Cumulative meta-analysis of epidermal growth factor receptor-tyrosine kinase inhibitors as first-line therapy in metastatic non-small-cell lung cancer.

We carried out a meta-analysis to evaluate the benefit of epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKI) over the standard first-line platinum-based chemotherapy for metastatic non-small-cell lung cancer (NSCLC). Studies that were considered eligible included controlled prospective randomized phase III studies in patients with NSCLC stages IIIB or IV. These patients received standard first-line platinum-based chemotherapy or EGFR-TKI; overall survival and progression-free survival (PFS) with adequate data were available to calculate and estimate the hazard ratio (HR) with a confidence interval (CI) of 95%. Eight studies were identified that compared EGFR-TKI versus standard first-line platinum-based chemotherapy to treat NSCLC in 2962 patients. Patients receiving EGFR-TKI showed significantly longer PFS [HR=0.266 (95% CI=0.20–0.35), P<0.0001]. No significant difference in overall survival [HR=0.946 (95% CI=0.35–2.53), P=0.912] was observed between the groups. The cumulative meta-analysis of the studies showed that, since 2011 (OPTIMAL study), the PFS benefit in the EGFR-TKI arm was statistically significantly longer. Toxicity values greater than or equal to 3 in the most prevalent EGFR-TKI group included skin rash, diarrhea, and increased aminotransferase. EGFR-TKI treatment significantly extends PFS, with acceptable toxicities than platinum-based chemotherapy. Thus, they should be considered as the first choice in the first-line treatment for patients with NSCLC and with the EGFR mutation.

Tegafur-uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: A proof of principle

Objective: The objective of this study was to evaluate the safety of using tegafur–uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. Patients and Methods: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m2/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. Results: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). Conclusion: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.

Chemotherapy-Induced Fatigue Correlates With Higher Fatigue Scores Before Treatment

Purpose: Cancer chemotherapy can induce fatigue in about 20% to 30% of patients. So far, there is very little information as to the predictors of chemotherapy-induced fatigue (CIF). We evaluated potential predictors of CIF in a sample of patients with cancer with several types of solid tumors scheduled to receive chemotherapy according to institutional protocols. Methods: Before their first and second chemotherapy cycles, patients answered to the Brief Fatigue Inventory (BFI), Chalder, Mini Nutritional Assessment (MNA), Stress thermometer, and HADS questionnaires as well as provided blood samples for inflammatory markers. Results: We evaluated 52 patients, 37 (71%) were female and mean age was 53 years. The most common tumors were breast cancer 21 (40%) and gastrointestinal tumors 12 (23%). Although 14 (25.2%) patients had an increase in their fatigue BFI scores equal or above 3 points from baseline, we observed no significant overall differences between BFI scores before and after chemotherapy. The only 2 factors associated with an increase of 3 points in the BFI scores after chemotherapy were race and higher baseline BFI levels. By multivariate analysis, overall BFI and Chalder scores after chemotherapy also correlated significantly with their respective baseline scores before treatment. HADS scores before treatment correlated with overall BFI scores postchemotherapy, whereas MNA scores before chemotherapy and female sex correlated with higher Chalder scores after treatment. Conclusion: We conclude that fatigue induced by chemotherapy is common and consistently associated with higher fatigue scores before treatment. Screening for fatigue before chemotherapy may help to identify patients who are prone to develop CIF.

Guarana (Paullinia cupana) Improves Anorexia in Patients with Advanced Cancer

ABSTRACT Purpose: Anorexia is prevalent in cancer patients with advanced disease. In this pilot phase II, open label, nonrandomized trial, we evaluated the efficacy and safety of guarana (Paullinia cupana) in patients with cancer and weight loss. Methods: We included advanced cancer patients with decreased appetite and weight loss of more than 5% from their baseline. All of the patients received 50 mg of the crude dry extract of guarana twice a day for 4 weeks. The trial was designed in two phases (Simon model). We considered a positive response in the first phase to be at least 5% weight gain or a three-point improvement in the appetite scale in at least three of the first 18 evaluable patients. Results: Of the 34 eligible patients, 30 were included and 18 completed the protocol. Only one patient abandoned the protocol due to toxicity (grade II arthralgia). No grade 3 or 4 toxicities and no significant differences in nausea, weight loss, or quality of life (FACT-G) occurred. Only two of the 18 patients who completed the study had weight gain above 5% from their baseline, whereas six patients had at least a 3-point improvement in the visual appetite scale. The M.D. Anderson Symptom Inventory (MDASI) was used to evaluate several symptoms, and we observed a significant decrease in the lack of appetite (p = 0.02) and in somnolence (p = 0.0142). Conclusion: We concluded that the weight stabilization and increased appetite that we observed in this study justify further studies of guarana in this patient population.