Cancer Chemotherapy and Pharmacology

FLAG vs FLAG-IDA: outcomes in relapsed/refractory acute leukemias Abstract Background FLAG (fludarabine, cytarabine, granulocyte colony—stimulating factor) and FLAG-IDA (idarubicin added to standard FLAG) are salvage chemotherapy regimens used for relapsed and refractory acute leukemias. The toxicity of the FLAG-IDA courses is generally more severe than for the FLAG courses, with marked neutropenia and thrombocytopenia. This study aims to compare the outcomes of both regimens in terms of morbidity, mortality and remission/transplant. No comparison has been reported so far in Pakistan or the rest of third world countries. Methodology This retrospective study was conducted in Hematology and Bone Marrow Transplant unit after approval from Institutional Review Board and Ethics Committee. 76 leukemic patients treated with salvage chemotherapy were included. Our endpoints for patient outcome analysis included disease remission/relapse, HSCT following remission, morbidity, mortality, progression free survival and overall survival. Kaplan Meier curves were made in SPSS for survival analysis. Results A total of 76 patients were included from 2015 to July 2018. 49 patients were given FLAG, and 27 were given FLAG-IDA. 31.6% in FLAG-IDA achieved complete remission (CR)/complete remission with incomplete counts (CRi). 21% in FLAG-IDA made it to Bone marrow transplant (BMT) (67% of those in CR/CRi). 41.7% in FLAG achieved CR/CRi, and 27.8% in FLAG made it to BMT (67% of those in CR/CRi). Common complications in both regimens were infection, bleeding and other complications e.g., rash, diarrhea, mucositis, etc. A statistically significant difference was found between overall survival of the two regimens, p value 0.033. Conclusions FLAG regimen was found superior to FLAG-IDA with better survival and subsequent transplant rate.

Short-time use of crizotinib as neoadjuvant in ALK-positive non-small cell lung carcinoma can be a chance for resectability Abstract Because of the rapid response to crizotinib, patients with ALK-positive locally advanced disease may become resectable with the use of neoadjuvant crizotinib. A 41-year-old never-smoking man who presented with asthma attack was found to have a suspicious lesion on chest X-ray after. Pathological examination was consistent with ALK(+), the signet-ring cell adenocarcinoma. Surgery was not performed because of mediastinal invasion of the mass. After 4 weeks of crizotinib treatment, a major response was achieved and the tumor became completely cavitary. Short-term neoadjuvant therapy with crizotinib for 4 weeks might be a promising therapy in locally advanced ALK-positive NSCLC and might provide a chance for resectability.

Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil Abstract Purpose Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. Methods We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m2) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). Results Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration–time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. Conclusion Rabeprazole does not affect capecitabine pharmacokinetics.

Phase II study to evaluate the efficacy of Trastuzumab in combination with Capecitabine and Oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial Abstract Purpose The phase III ToGA trial established cisplatin, fluoropyrimidine and trastuzumab as the standard treatment in HER2-positive advanced gastric cancer (AGC). However, as demonstrated in HER2-negative AGC, oxaliplatin-based regimens could improve tolerance remaining effective. The aim of this trial was to explore the potential activity and safety of capecitabine, oxaliplatin (XELOX) and trastuzumab in patients with HER-2 positive advanced gastric cancer. Methods We conducted a multicentre, prospective, non-randomised, non-controlled, open-label and national (Spanish) phase II study. Patients with HER2-positive advanced gastric or gastro-oesophageal junction (EGJ) cancer received XELOX and trastuzumab as first-line treatment. Primary endpoint was objective tumour response rate (ORR). Results 45 patients from ten hospitals in Spain were included from September 2011 to December 2013. Median age was 65 years, 82.2% were male, 69% had gastric cancer and 31% had EGJ tumours. At a median follow-up of 13.7 months (7.1–20.9), the estimated median progression-free survival and overall survival were 7.1 (95% CI 5.5–8.7) and 13.8 months (95% CI 10.1–17.4), respectively, with 8.9%, 37.8% and 31.1% of patients achieving complete response, partial response and stable disease. Regarding safety, 44.4% of the patients had grade 3 or greater adverse events, being the most frequent diarrhoea (26.6%), fatigue (15.5%), nausea (20%) and vomiting (13.3%). Only two patients (4.4%) developed asymptomatic grade 2 left ventricle ejection fraction reduction. Conclusions XELOX-trastuzumab is a promising and effective therapy as first-line treatment for patients with HER2-positive AGC, with comparable results to the ones obtained with other "platinum-based" regimens. This scheme is feasible and tolerable with a low incidence of cardiac toxicity.

d,l -Methadone does not improve radio- and chemotherapy in glioblastoma in vitro Abstract Purpose Glioblastoma (GBM) is the most common malignant tumor of the central nervous system. Median survival of glioblastoma patients under standard therapy including radiotherapy and chemotherapy using temozolomide (TMZ) is 14.6 months. As cell culture experiments combining d,l-methadone with doxorubicin demonstrated an increased reduction of cell viability of glioblastoma cells, the opioid has been discussed as a drug for the treatment of GBM. Despite lack of clinical and experimental evidence that d,l-methadone in combination with standard therapy will be beneficial, an increasing number of tumor patients medicating themselves with d,l-methadone present to the hospitals in Germany. Methods As a first step towards understanding whether d,l-methadone may increase the efficacy of standard therapy, we used a cell culture model of primary GBM and fibroblast cell cultures derived from GBM patients. The cultures were treated with different concentrations of d,l-methadone in combination with X-irradiation, TMZ or both. Cell viability was determined by measuring ATP in cell lysates and dehydrogenase activity in living cells. Results When only treated with d,l-methadone, 1 µM of the opioid was sufficient to reduce viability of fibroblasts, whereas 10 µM was needed to significantly reduce glioblastoma cell viability. In addition, d,l-methadone did not improve the anti-neoplastic effects of X-irradiation, temozolomide or both. Conclusions As d,l-methadone reduces glioblastoma cell viability only when concentrations are used that had been reported to be toxic to patients and as there were no interactions observable combining it with standard therapy, a recommendation for the use of d,l-methadone in glioblastoma therapy cannot be given.

Docetaxel, cisplatin, and 5-fluorouracil combination chemoradiotherapy for patients with cervical esophageal cancer: a single-center retrospective study Abstract Background To evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for cervical esophageal cancer (CEC), we performed a retrospective analysis of CEC patients treated by DCF-RT at a single institution. Methods We conducted a single-center retrospective study. Twenty-one patients with CEC who underwent DCF-RT between 1999 and 2017 at our institute were included in this study. Chemotherapy consisted of intravenous docetaxel at 50 mg/m2 on day 1, intravenous CDDP at 60 mg/m2 on day 1, and intravenous 5-FU at 600 mg/m2 on days 1–4, repeated every 4 weeks for two cycles. Among the 21 patients, six were irradiated using three-dimensional conformal RT (3D- conformal RT) and 15 were treated using intensity-modulated RT (IMRT) consisting of 60 Gy in 30 fractions. Results The median follow-up period was 49.6 months (range 4.6–97.6). The overall complete response (CR) and local CR rates were 61.9% and 81.0% for all patients, and 76.9% and 84.6% for patients without hypopharyngeal and/or thoracic esophageal invasion, respectively. The 3-year overall survival (OS), progression-free survival (PFS), and local failure-free survival (LFFS) rates were 79.6, 52.4, and 74.7%, respectively. Grade 3–4 leucopenia developed in 12 patients (70.6%), neutropenia developed in 13 patients (81.2%), and mucositis developed in 2 patients (9.5%). There were no treatment-related deaths. Conclusions The 3-year OS and LFFS of patients who underwent DCF-RT were higher than those in the previous studies. Although the high rate of myelosuppression requires careful management, DCF-RT is a safe and effective modality for CEC.

Apatinib for chemotherapy-refractory extensive-stage SCLC: a retrospective study Abstract Purpose There is no standard treatment strategy for patients with extensive-stage small cell lung cancer (SCLC) who have failed two or more prior chemotherapeutic regimens. In this study, we retrospectively evaluated the efficacy and safety of apatinib in patients with extensive-stage SCLC after failure of more than second-line chemotherapy. Methods A study group comprised of 22 patients with extensive-stage SCLC after failure of more than two prior chemotherapeutic regimens was given apatinib orally at an initial dose of 500 mg daily until disease progression or unacceptable toxicity. This study was analyzed according to the National Cancer Institute Common Toxicity Criteria for adverse events (AEs) and Response Evaluation Criteria in Solid Tumors (RECIST) for response assessment. Results Between August 30, 2015, and May 26, 2017, 22 patients were enrolled for evaluating the efficacy and safety of apatinib. Among them, 12/22 (54.5%) underwent dose reduction during treatment. Up to July 31, 2018, the median progression-free survival rate was 135.0 days [95% confidence interval (CI) 63.8–206.2]. According to the RECIST criteria, the disease control rate (DCR) was 86.4%, 19/22 [comprised of partial response (PR) 18.2%, 4/22; and stable disease (SD) 68.2%, 15/22 patients]. The most frequent AEs were hand–foot syndrome (45.5%, 10/22), secondary hypertension (45.5%, 10/22) and fatigue (40.9%, 9/22). The primary grade 3 or 4 toxicities were hypertension (22.7%, 5/22), hand–foot syndrome (13.6%, 3/22), and proteinuria (9.1%, 2/22). Conclusions Apatinib exhibits modest activity and acceptable toxicity for patients with heavily pretreated extensive-stage SCLC.

Pharmacokinetic and exploratory exposure–response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study Abstract Purpose To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G). Methods A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E–R analysis. Results Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs. Conclusion Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.

Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer Abstract Purpose Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC. Methods We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells. Results We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells. Conclusions PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.

A phase I study of gemcitabine + dasatinib (gd) or gemcitabine + dasatinib + cetuximab (GDC) in refractory solid tumors Abstract Purpose This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients. Methods This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m2 weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m2 weekly after a loading dose of cetuximab of 400 mg/m2. There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment. Results Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3–4 neutropenia (n = 7), Gr 4 colitis (n = 1), Gr 3 bilirubin (n = 2), Gr 3 anemia (n = 2), Gr 3 thrombocytopenia (n = 2), Gr 3 edema/fluid retention (n = 1), and Gr 3 vomiting (n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1–7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels. Conclusions The MTD/RPTD of GD is gemcitabine 1000 mg/m2 weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.