Combinations Of Cytotoxic Drugs Research Articles

Sequential release of epigallocatechin gallate and paclitaxel from PLGA-casein core/shell nanoparticles sensitizes drug-resistant breast cancer cells

Nanomedicines consisting of combinations of cytotoxic drugs and molecular targeted therapeutics which inhibit specific downstream signals are evolving as a novel paradigm for breast cancer therapy. This research addresses one such combination of Paclitaxel (Ptx), having several adversities related to the activation of NF-κB pathway, with Epigallocatechin gallate (EGCG), a multiple signaling inhibitor, encapsulated within a targeted core/shell PLGA-Casein nanoparticle. The sequential release of EGCG followed by Ptx from this core/shell nanocarrier sensitized Ptx resistant MDA-MB-231 cells to Ptx, induced their apoptosis, inhibited NF-κB activation and downregulated the key genes associated with angiogenesis, tumor metastasis and survival. More importantly, Ptx-induced expression of P-glycoprotein was repressed by the nanocombination both at the protein and gene levels. This combination also offered significant cytotoxic response on breast cancer primary cells, indicating its translational value. From the Clinical EditorBreast cancer is the most common cancer in women worldwide. As well as surgery, chemotherapy plays a major role in the treatment of breast cancer. The authors investigated in this article the combination use of a chemotherapeutic agent, Paclitaxel (Ptx), and an inhibitor of NF-?B pathway, packaged in a targeted nano-based delivery platform. The positive results provided a new pathway for future clinical use of combination chemotherapy in breast cancer.

Lapatinib enhances the cytotoxic effects of doxorubicin in MCF-7 tumorspheres by inhibiting the drug efflux function of ABC transporters

Increasing evidences indicate that cancer stem cells are resistant to chemotherapy due to their cell quiescence and the expression of ATP-binding cassette (ABC) transporters. In this study, we utilized tumorsphere cultures to seek better strategies to overcome chemoresistance since tumorsphere cultures have been used widely for the enrichment of cancer stem cells. We found that tumorspheres generated from MCF-7 human breast cancer cells exhibited high proportions of quiescent cells and expressed MDR-1 at elevated levels, leading to resistance to 5-fluorouracil, paclitaxel, and doxorubicin. Because the expression of EGFR/HER2 was increased in MCF-7 tumorspheres, we assessed the combinational effect of the dual ErbB1/ErbB2 inhibitor, lapatinib, with doxorubicin in tumorspheres. The results showed that inhibition of EGFR/HER2 signaling by lapatinib sensitized MCF-7 tumorspheres to doxorubicin by inhibiting the expression of the ABC transporters, MDR-1 and BCRP, and thus, enhancing the intracellular accumulation of doxorubicin. These findings suggest that combinations of lapatinib and cytotoxic anticancer drugs may offer an advantage for treating the drug-resistant cancers.

Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo

TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to chemo-resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 and etoposide in the presence or absence of BDNF in vitro and cell survival was determined. NB xenograft tumors were treated with AZD6918 and etoposide, either alone or in combination in vivo, and the anti-tumor growth effect or mice survival advantage was evaluated. Our study showed that AZD6918 induced cell death as a single agent and attenuated BDNF/TrkB-induced protection from etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect or survival advantage in vivo, a combination of AZD6918 and etoposide had a statistically significant stronger anti-tumor growth effect and survival advantage compared to treatment with either agent alone. Our data indicate that as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These results extend the spectrum of cytotoxic drugs whose efficacy is increased in combination with Trk inhibitors and support the combination of Trk inhibitors and cytotoxic drugs for NB treatment.

Antitumor effects of different administration sequences of cisplatin and Endostar on Lewis lung carcinoma.

Angiogenesis plays an essential role in the growth and metastasis of a number of tumors. Anti-angiogenic drugs are able to normalize tumor vasculature and inhibit tumor growth. Therefore, it has been hypothesized that the combination of cytotoxic chemotherapy drugs and angiogenesis inhibitors may exert complementary therapeutic benefits in the treatment of cancer. In the present study, the effect of the angiogenesis inhibitor, recombinant human endostatin (Endostar), in combination with cisplatin, was evaluated in C57/BL/6 mouse xenografts under different administration sequences. The drug combinations and sequences of administration were analyzed within the cancer xenografts for any inhibitory effects. Changes in the cell cycle distribution of the cells were monitored using flow cytometry. The effects of Endostar, particularly a reduction in the density of microvessels, were assessed using a method that employed anti-cluster of differentiation 31 antibodies. The concentration of cisplatin in the blood and tumor tissue at various time-points following administration was detected by high-performance liquid chromatography. The tumor tissues that received simultaneous Endostar and cisplatin exhibited increased inhibition of tumor growth and improved cell cycle distribution compared with those that received cisplatin alone, or those in which Endostar was administered prior to cisplatin. The simultaneous administration of the drugs resulted in the lowest microvessel density in the xenografts. Under these conditions, the concentration of cisplatin was revealed to be the highest in the grafted tumor tissue. The results of the present study suggest that the co-administration of Endostar and cisplatin may aid in the optimization of the antitumor activity of cisplatin.

P3-1-4 - Safety Profile of the Desensitizing Carboplatin Infusion for Patients Documented Carboplatin Hypersensitivity

Background: The combination of carboplatin and other cytotoxic drug is the current standard chemotherapy regimen for platinum sensitive recurrent epithelial ovarian, and peritoneal cancer. Hypersensitivity reaction (HSR) is one of adverse events of platinum agents. Because repeated exposure to platinum agents, particularly carboplatin, is associated with development of HSR, it is often difficult to use continuous platinum combination therapy.On the other hands, Peter G Rose et al. had reported successful administration of carboplatin with desensitizing method for clinically documented carboplatin HSR. This report aims to assess the safety of the carboplatin desensitizing therapy through the analysis in single institution.Method: We reviewed medical record, and evaluated the safety profile of the carboplatin desensitizing therapy for the patients with platinum sensitive recurrent epithelial ovarian, and peritoneal cancer, who had history of HSR of carboplatin. The carboplatin dose was administrated with 1/1000th of the total carboplatin dose infused 60min in turn was followed by 1/100th and 1/10th infused 60min. The remaining dose was infused 2h. Patients were pretreated with 20mg intravenous dexamethasone prior to the initiation of carboplatin.Results: Between Feb 2012 and Jan 2014, 14 patients whose First HSR had occurred median 17 courses (range 8-43); Grade 1 8%, Grade 2 25%, Grade 3 33%, Grade 4 33%, received total 72 courses of carboplatin contained regimen. 9 patient, 59 courses were successfully rechallenged while 5 patients, 13 coarses had a recurrent carboplatin hypersensitivity; Grade 1 8%, Grade 2 8%, Grade 3 2%. All cases in which HSR recurred were handled with termination of the carboplatin infusion, followed by intravenous steroids and antihistamines with successful resolution, and were able to completely administrate carboplatin with slow infusion.Conclusion: A CBDCA desensitizing carboplatin infusion regimen is safe and well tolerated.

Abstract 1785: Distinct effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae

Abstract Anthracyclines are common chemotherapeutic agents used in many cancers which are refractory to other therapeutic alternatives. In triple negative breast cancer which is commonly observed in African-American women (AA) and tend to be more aggressive, carry worse prognoses and are harder to manage because they lack the molecular targets required for therapies, anthracyclines are some of the few therapeutic alternatives. Although effective, resistance to this agent usually arises and serious side-effects like the development of cardiomyopathy limits their use. To increase our knowledge of the pathways that protect cells from anthracyclines we carried out a genome-wide genetic screening in the eukaryotic model organism S. cerevisiae to identify gene defects that generate cells hypersensitive to doxorubicin. A total of 71 deletion strains displayed varying levels of sensitivity to anthracyclines. Among these, mutants of HOM6 confer significant increased sensitivity to doxorubicin. This effect appears to be due to the accumulation of the threonine intermediate L-aspartate-semialdehyde and can be abolished by the inactivation of a prior step, involving HOM3, which prevents the accumulation of the intermediate. In order to further characterize the synergism of aldehydes and doxorubicin, we have tested the effect of different aldehydes on the cytotoxicity of cells exposed to anthracyclines. Our data show that treatment with formaldehyde (2 mM) reduced the survival of the wild type strain to 78%. However, in the presence of doxorubicin, formaldehyde reduced the viability of the strain by between 31 to 39-fold (with 10 µM doxorubicin) relative to doxorubicin and formaldehyde alone and by ∼110-fold relative to doxorubicin at 150 µM concentration. Co-treatment with formaldehyde and doxorubicin of anthracycline-resistant strains siz1 and msh2 also shows increased toxicity. However, the synergistic effect is not as pronounced in these strains compared to the wild type. Among the aldehydes tested, formaldehyde was most effective. Glutaraldehyde and acetaldehyde displayed distinct effect on strains siz1, and ald5. The potential use of a combination of aldehydes and cytotoxic drugs could potentially lead to applications intended to enhance anthracycline-based therapy. This possibility will be discussed, as well as the targeting of aldehydes in relevant human pathways. Research supported by NIH/NCRR RCMI grant #RR03020 at Florida A&M University. Citation Format: Jana Sharrae Miles, Tryphon Mazu, Selina Darling-Reed, Hernan Flores-Rozas. Distinct effect of aldehydes in anthracycline cytotoxicity in S. cerevisiae. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1785. doi:10.1158/1538-7445.AM2014-1785

Bendamustine in mantle cell lymphoma

SUMMARY Mantle cell lymphoma (MCL) is generally considered incurable and has the worst overall survival among B-cell lymphoma subtypes. The disease usually responds well to initial therapy but most patients relapse and then respond only briefly to salvage therapy. Nevertheless, the median overall survival of MCL patients has dramatically improved from 2 to 3 years of the 90’s to more than 5 years at present. This improvement was due either to the introduction of dose-intensive strategies and/or high-dose therapy upfront in younger patients, and to the availability of novel agents in older patients or in the relapsed/refractory setting. Bendamustine, mostly in combination with rituximab, has been recently introduced in the armamentarium for treating patients with MCL with surprising results. Its efficacy and tolerability compare favorably with any other cytotoxic drug or drug combinations for treating patients with MCL, as summarized in this review. Due to its favorable toxicity profile, bendamustine is now increasingly combined with other active compounds. Cytosine arabinoside, which is well known for its striking activity in younger patients with MCL, has been combined with bendamustine in the rituximab, bendamustine and cytarabine (R-BAC) regimen with promising results. Other novel agents, that are approved in Europe or in the United States for the treatment of MCL, like bortezomib, lenalidomide, temsirolimus, and drugs targeting the B-cell receptor pathway (idelalisib, ibrutinib), are under investigation in combination with bendamustine. These molecules provide an opportunity to build up on the regimens used in MCL either in combination with bendamustine upfront, or as maintenance, and will open new frontiers in the treatment of patients with MCL.

P0203 Anticancer effect of bromelain alone and in combination with cisplatin or fluorouracil on malignant peritoneal mesothelioma cells

Background Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum that is causally related to asbestos exposure. Nonspecific symptoms and late diagnosis result in poor survival ( Methods MUC1 expression was assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. Cell lines were treated with various concentrations of bromelain, and after 4 h and 72 h their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or fluorouracil) and their viability assessed at 72 h. The effects of bromelain on cellular survival proteins were investigated with western blotting. Findings PET cells expressed more MUC1 than YOU cells. Cell viability of both PET and YOU cells were adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, combining fluorouracil with bromelain did not show a significant increase in cytotoxicity. Bromelain induced cell death via apoptosis and autophagy. Interpretation Bromelain has potential as a therapeutic agent in malignant peritoneal mesothelioma.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

SummaryBackgroundAdvanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.MethodsCOIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.FindingsWe registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).InterpretationCetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.FundingUK Medical Research Council, Merck KGaA.

Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapy.

Electroporation is used to enhance drug diffusion and gene delivery into the cytosol. The combination of electroporation and cytotoxic drugs, electrochemotherapy (ECT), is used to treat metastatic tumor nodules located at the skin and subcutaneous tissue. The objective response rate following a single session of treatment exceeds 80%, with minimal toxicity for the patients. The efficacy of ECT in the bone and visceral metastasis is currently investigated, and Phase II studies have been completed. ECT has been used to treat skin primary tumors, except melanoma, and is under investigation for locally advanced pancreatic cancer. Early evidence suggests that treatment of tumor nodules with ECT recruits components of the immune system and eliciting a systemic immune response against cancer is a challenging clinical perspective. Considering the proven safety in several different clinical applications electroporation should be viewed as a clinical platform technology with wide perspectives for use in ECT, gene therapy and DNA vaccination.

Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells

Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3-5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

Reversal of attachment to or invasion of major intrahepatic vessels by colorectal liver metastases according to prehepatectomy chemotherapy regimen

Tumor reduction by present-day prehepatectomy chemotherapy can render initially unresectable disease resectable. However, little is known about whether effects on liver metastases with radiologically defined "attachment to or invasion of" major intrahepatic vessels differ between chemotherapy regimens with or without monoclonal antibodies. We compared histologically the relationships between liver tumors and major intrahepatic vessels after chemotherapy according to regimens used to treat colorectal liver metastasis. In 38 patients who underwent chemotherapy and hepatectomy with pretreatment images showing metastases attached to or invading major intrahepatic vessels, 62 metastases showed attachment to or invasion of 88 vessels. After resection, attachment, invasion, and separation were determined histopathologically in resected specimens. Thirteen patients received cytotoxic drug combinations alone, whereas 25 were treated with regimens including a monoclonal antibody (bevacizumab in 15 and cetuximab in 10). By imaging, 16% (5/32) of vessels in patients receiving cytotoxic drugs alone, 23% (8/35) of vessels in those also receiving bevacizumab, and 48% (10/21) of vessels in those also receiving cetuximab showed detachment after chemotherapy (P = .015 for cetuximab versus cytotoxic and P = .039 for cetuximab versus bevacizumab). Excluding 8 vessels not evaluated histologically, 23 of 31 vessels in the cytotoxic group remained attached or invaded, as did 16 of 29 in the bevacizumab group and 8 of 20 vessels in the cetuximab group (P = .05 versus cytotoxic). Prehepatectomy chemotherapy regimens including monoclonal antibodies, particularly anti-epidermal growth factor receptor antibodies, eradicated attachment or invasion between vessels and metastases more frequently. Individualized strategies for prehepatectomy chemotherapy based on intrahepatic location of metastases may offer advantages according to proximity of the metastases to the major intrahepatic vessels.

Abstract P3-13-01: Primary efficacy endpoint analysis of the CARIN trial: Capecitabine (Cap) and bevacizumab (Bev) with or without vinorelbine (Vin) in first line metastatic breast cancer (MBC)

Abstract Background: In RIBBON-1, the combination of Bev with Cap as 1st-line therapy for MBC significantly improved progression-free survival (PFS) compared with Cap alone, with limited impact on tolerability. Vin and Cap are active agents with few overlapping toxicities. The combination of both cytotoxic drugs in phase I/II trials showed good tolerability and promising clinical activity. The CARIN trial aims to further improve efficacy by adding Vin to Cap/Bev to establish a less toxic alternative to taxane-based 1st line therapy. Patients and Methods: CARIN is a multicenter randomized study comparing the efficacy of Cap plus Bev versus the same regimen combined with Vin. From 04/2009 until 10/2012 598 pts in 61 participating centers were randomized (1:1) to receive Cap 1000 mg/m2 bid days 1–14 + Bev 15 mg/kg q3w (Arm A) or Cap/Bev combined with Vin 25 mg/m2 days 1+8 (Arm B). Randomization was stratified by prior therapy with anthracycline and/or taxane (yes/no) and hormone receptor status (ER/PR +/-). Treatment was continued until progression or unacceptable toxicity. Key eligibility criteria included Her-2 negative metastatic or locally recurrent disease, no prior palliative chemotherapy for MBC, ECOG ≤2, and absence of brain metastases. Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate, overall survival, and safety &amp; tolerability. Baseline demographics, prior therapy and disease characteristics were well balanced. 21.5% of pts had triple negative BC, 10.6% had bone metastases only. Progression free survival data for the two treatment arms will be compared using a log-rank test. The influence of pretreatment, hormone receptor status and predictive variables on progression free survival will be analyzed within a cox regression model. Results: Data Cleaning and analysis will be complete by October 2013 and results for the primary endpoint PFS and secondary endpoints will be presented at the meeting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-01.

Abstract C177: TAS-117, a highly selective non-ATP competitive inhibitor of AKT demonstrated antitumor activity in combination with chemotherapeutic agents and molecular targeted drugs.

Abstract Background: TAS-117 is a potent and highly selective non-ATP competitive small molecule inhibitor of AKT. AKT controls cellular proliferation and resistance to apoptosis, and is known to be activated in patients with relapsed or refractory tumors. Thus the combination of TAS-117 and cytotoxic drugs could be a promising approach to treat cancers. In addition, recent preclinical and clinical studies suggest that the vertical inhibition of key cancer signaling pathways may be an effective way to minimize crosstalk signaling and compensatory feedback activation. Therefore, we evaluated these combination approaches using TAS-117. Materials and Methods: A PTEN negative human ovarian cancer cell line A2780 and HER2 overexpressing human gastric cancer cell lines NCI-N87 and 4-1ST were used. In vitro combination studies were conducted by using CellTiter Glo™ assays. For in vivo studies, cells were subcutaneously transplanted into the side flank of nude mice. TAS-117, S-1, lapatinib, and everolimus were given by daily oral dosing. Carboplatin and irinotecan were given by weekly i.v. bolus injection. Trastuzumab was given by weekly i.p. bolus injection. Tumor volumes and body weights were measured twice a week. Apoptosis induction and pathway inhibition were determined by immunoblotting. Results: The in vitro combination studies revealed that TAS-117 enhanced the cytotoxicity of cisplatin, SN38, and fluorouracil in A2780 cells. In vivo, TAS-117 significantly improved the antitumor effect of carboplatin or irinotecan in an A2780 xenograft model. TAS-117 also enhanced the antitumor effect of S-1 in a 4-1ST xenograft model. With downstream, mTOR inhibitor everolimus, TAS-117 exhibited synergistic growth inhibition in NCI-N87 cells. Interestingly, cleavage of PARP was induced by the combination of TAS-117 and everolimus but not by either single agent alone. Enhanced antitumor activity in combination with TAS-117 and everolimus was confirmed in the NCI-N87 xenograft model. With an upstream, HER2 inhibitor lapatinib, TAS-117 also exhibited synergistic growth inhibition in vitro and enhanced antitumor activity in vivo in the NCI-N87 model. The combinatorial effect of TAS-117 and HER2 blockade was further evaluated using trastuzumab. TAS-117 strongly enhanced the antitumor effect of trastuzumab in a 4-1ST xenograft model. Conclusion: TAS-117 was effective in combination with chemotherapeutic agents including paclitaxel, carboplatin, irinotecan and S-1. Vertical pathway inhibition by TAS-117 with trastuzumab, lapatinib and everolimus were also effective. Our studies provide a strong rationale for clinical evaluation of our highly selective AKT inhibitor TAS-117 in combination with chemotherapeutic agents and molecular targeted drugs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C177. Citation Format: Koji Ichikawa, Tetsuya Abe, Hideki Nagase, Hitoshi Saito, Ryouto Fujita, Megumu Okada, Kazuhiko Yonekura, Toshiyasu Shimomura, Teruhiro Utsugi. TAS-117, a highly selective non-ATP competitive inhibitor of AKT demonstrated antitumor activity in combination with chemotherapeutic agents and molecular targeted drugs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C177.

Combination of Cytotoxic Drugs for Patients with HER2-Negative Metastatic Breast Cancer

In the last few decades the approach to metastatic breast cancer (MBC) treatment using chemotherapy, either as single or combination agents, has been largely studied and a wide spectrum of therapeutic options is now available. Anthracyclines and taxanes remain the cornerstone of treatment in this setting. The choice of combination chemotherapy versus monochemotherapy is still open to debate since results from clinical trials are, unfortunately, conflicting. Despite improvements in response and disease-free survival rates, there has been no overall survival benefit reported although toxicity is increased. Therefore, based on available data, clinical decision-making for a busy practitioner should consider not only patient/tumor characteristics and the potential benefits of treatments, but also their toxicity profiles and patient preferences. Novel cytotoxic compounds have been approved for clinical use and combination regimens incorporating these agents may bring new treatment opportunities for MBC patients. In this review, we summarize the main achievements and the currently available and future combinations of cytotoxic drugs for patients with HER2-negative MBC.

Transarterial Chemoembolization - Status Quo in Germany

Against the background of the current preparation of the national disease management guideline for the diagnosis and treatment of hepatocellular carcinoma (HCC), the German Society for Interventional Radiology (DEGIR) launched a statewide survey in order to evaluate the current status of transarterial chemoembolization (TACE) in Germany. In April 2012 an e-mail questionnaire relating to TACE practices in patients with intermediate-stage HCC was sent to all chief physicians of interventional radiology departments in Germany that were members of DEGIR. 96 questionnaires were completed and evaluated statistically. The most frequent combinations of embolic agents and cytotoxic drugs are drug-eluting beads combined with doxorubicin or epirubicin as well as lipiodol plus doxorubicin, epirubicin or cisplatin. 60 % of the interventionalists prefer superselective chemoembolization. In most cases more than one chemoembolization per patient is performed (95.5 %). The most common (77 %) time interval between two interventions ranges between one and two months. The results of this survey show the often stated criticism in Germany regarding the substantial differences in TACE protocols and highlight the importance of standards of practice for TACE in patients with HCC.

Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).

e19147 Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.

Keynote Address IV: Radiotherapy of head-and-neck cancer: From translational research to clinical optimization

Nowadays, managing head-and-neck cancer encompasses complex, multi-modality approaches, articulated around three main therapeutic pillars, namely surgery, radiotherapy and systemic treatments. Since the first applications of radiotherapy, in the 1920s at the Curie Institute, to patients with laryngeal tumors, head-and-neck cancer irradiation has been characterized by constant advances in terms of both technological and strategic breakthroughs. Under the impulsion of G.H. Fletcher in Houston, the combination of surgery and radiotherapy was the first real “concerted action” implemented in patients presenting with locally advanced disease, paving the way for both pre-operative and adjuvant strategies. About twenty years after the advent of high-energy beams, the refinement of irradiation techniques, essentially through the progressive shift from 2D- to 3D-conformal treatment planning and delivery, led the radio-oncology community to investigate the role of intensified schedules of irradiation, as definitive approach in patients with stage III–IV disease. In the early 1980s, EORTC successfully pioneered the use of hyperfractionated and accelerated regimes, followed by the implementation of very strong acceleration such as CHART in United Kingdom. Increasing cell killing and/or counterbalancing the tumor repopulation rates without affecting significantly the impact of irradiation on normal tissues were the declared objectives of the so-called “alteration of fractionation”, objectives which were met in a significant number of both institutional and cooperative trials. The combination of cytotoxic drugs and radiotherapy was the next field of investigation, launched about 25 years ago, first through a phase of “learning curve” characterized by a significant acute morbidity, and thereafter by the level I of evidence reached in adjuvant setting with the results of EORTC and RTOG trial comparing the co-administration of radiation and cisplatin with postoperative radiotherapy alone. The concept of hitting concurrently various therapeutic targets was actually reinforced by these results, and the era of bio-radiation, based on targeted therapies combined to radiation, could begin. At the turn of the century, the progressive introduction of intensity-modulated radiation therapy (IMRT) met a number of requirements to increase the therapeutic ratio of irradiation-based strategies, especially as regards a significant sparing of radio-sensitive structures like salivary glands, larynx, and skull base. Undoubtedly these highly conformal approaches nowadays represent an inflexion point for the role of radiotherapy in head-and-neck oncology, also in terms of quality of life for these patients. This Lecture will revisit these achievements and propose a critical appraisal of the complex management of this complex disease, without forgetting what could be, in the future, the parameters of choice to integrate even more successfully this discipline into strategies better tailored to clinical and biological features and risk levels.

Enhancing Doxorubicin-Induced MCA-Fibrosarcoma Cytotoxicity by an Eriobotrya japonica Hydrophilic Butanol-Treated Extract through Natural Killer Cells Activation

The combination of cytotoxic drugs with immunotherapy should be more effective than monotherapy alone since both therapeutic modalities may target different mechanisms. In addition, combination therapy may reduce adverse events associated with cytotoxic drugs. Eriobotrya japonica hydrophilic butanol-treated extract (EJWR) was found to modulate cytokines by enhancing IL-12, IFN-γ and TNF-α in vitro and in vivo and within tumor microenvironment. This was associated with enhancing survival time of mice bearing intra-peritoneal MCA fibrosarcoma (MCA FS). In the present work, we evaluated the combination of EJWR with doxorubicin (Dox) on MCA FS cytotoxicity using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay in the absence and presence of spleen cells or Natural Killer (NK) lymphocytes from tumor bearing mice. The results showed that Dox exhibited mild cytotoxicity to healthy spleen cells and EJWR reversed such cytotoxicity. In addition, increasing concentrations of Dox induced 40% (p<0.01) MCA FS cytotoxicity. This percent increased significantly to 60% at Dox 5 μM when co-cultured with NK cells from tumor bearing mice and increased further to 80% (p<0.01) when Dox was combined with EJWR. The latter increase in cytotoxicity was significantly (p<0.01) higher than each agent alone. This enhancement was associated with significant production of TNF-α and retaining IFN-γ levels from NK cells lysates. This concluded that the immunomodulator, EJWR, mediates NK activation and enhances Dox- induced MCA FS cytotoxicity.

Functional polymorphisms in xenobiotic metabolizing enzymes and their impact on the therapy of breast cancer.

Breast cancer is the top cancer among women, and its incidence is increasing worldwide. Although the mortality tends to decrease due to early detection and treatment, there is great variability in the rates of clinical response and survival, which makes breast cancer one of the most appealing targets for pharmacogenomic studies. The recognition that functional CYP2D6 polymorphisms affect tamoxifen pharmacokinetics has motivated the attempts of using CYP2D6 genotyping for predicting breast cancer outcomes. In addition to tamoxifen, the chemotherapy of breast cancer includes combinations of cytotoxic drugs, which are substrates for various xenobiotic metabolizing enzymes. Because of these drugs’ narrow therapeutic window, it has been postulated that impaired biotransformation could lead to increased toxicity. In the present review, we performed a systematic search of all published data exploring associations between polymorphisms in xenobiotic metabolizing enzymes and clinical outcomes of breast cancer. We retrieved 43 original articles involving either tamoxifen or other chemotherapeutic protocols, and compiled all information regarding response or toxicity. The data indicate that, although CYP2D6 polymorphisms can indeed modify tamoxifen pharmacokinetics, CYP2D6 genotyping alone is not enough for predicting breast cancer outcomes. The studies involving other chemotherapeutic protocols explored a great diversity of pharmacogenetic targets, but the number of studies for each functional polymorphism is still very limited, with usually no confirmation of positive associations. In conclusion, the application of pharmacogenetics to predict breast cancer outcomes and to select one individual’s chemotherapeutic protocol is still far from clinical routine. Although some very interesting results have been produced, no clear practical recommendations are recognized yet.