Non-platinum-based chemotherapy for treatment of advanced gastric cancer:5-fluorouracil,taxanes,and irinotecan

Despite numerous advances in treatment options,advanced gastric cancer(AGC)remains a major public health issue and the leading cause of cancer-related deaths.Cisplatin is one of the most effective broadspectrum anticancer drugs for AGC and a doublet combination regimen of either cisplatin-based or 5-fluorouracil(5FU)-based chemotherapy is generally used for treatment of patients with AGC.However,there is still no consensus on the best regimen for treating AGC.Recently,various new chemotherapeutic agents,including oral 5FU,taxanes,and irinotecan,have been identified as improving the outcomes for AGC when used as a single agent or in combination with nonplatinum chemotherapy.Nonetheless,it is still unclear whether non-platinum-based chemotherapy is a viable treatment option for patients with AGC.Accordingly,this review focuses on the efficacy and tolerability of non-platinum-based chemotherapy for patients with AGC.

Breakthrough therapy for peritoneal carcinomatosis of gastric cancer:Intraperitoneal chemotherapy with taxanes

The effect of chemotherapy on peritoneal carcinomatosis(PC) of gastric cancer remains unclear.Recently,the intraperitoneal(IP) administration of taxanes [e.g.,paclitaxel(PTX) and docetaxel(DOC)] during the perioperative period has shown promising results.Herein,we summarized the rationale and methodology for using IP chemotherapy with taxanes and reviewed the clinical results.IP administered taxanes remain in the IP space at an extremely high concentration for 48-72 h.The drug directly infiltrates peritoneal metastatic nodules from the surface and then produces antitumor effects,making it ideal for IP chemotherapy.There are two types of perioperative IP chemotherapy with taxanes: neoadjuvant intraperitoneal and systemic chemotherapy and sequential perioperative intraperitoneal chemotherapy(SPIC).In SPIC,patients receive neoadjuvant IP chemotherapy and the same regimen of IP chemotherapy after cytoreductive surgery(CRS) until disease progression.Usually,a taxane dissolved in 500-1000 m L of saline at ordinary temperature is administered through an IP access port on an outpatient basis.According to phase Ⅰ?studies,the recommended doses(RD) are as follows: IP DOC,45-60 mg/m2; IP PTX [without intravenous(IV) PTX],80 mg/m2; and IP PTX(with IV PTX),20 mg/m2.Phase Ⅱ studies have reported a median survival time of 14.4-24.6 mo with a 1-year overall survival of 67%-78%.A phase Ⅲ study comparing S-1 in combination with IP and IV PTX to S-1 with IV cisplatin started in 2011.The prognosis of patients who underwent CRS was better than that of those who did not; however,this was partly due to selection bias.Although several phase Ⅱ studies have shown promising results,a randomized controlled study is needed to validate the effectiveness of IP chemotherapy with taxanes for PC of gastric cancer.

Unfavorable Pathological Complete Response Rate of Neoadjuvant Chemotherapy Epirubicin plus Taxanes for Locally Advanced Triple-negative Breast Cancer

Anthracycline-Taxane chemotherapy is widely used in neoadjuvant treatment for breast cancers. However, there is limited data reported in patients with triple negative breast cancer （TNBC）. Here, we evaluated the pathologic responses and survival of neoadjuvant epirubicin and taxanes chemotherapy in patients with locally advanced TNBC to provide some useful information for clinical practice. A total of 43 patients with locally advanced TNBC were enrolled in this study. Patients were administered with epirubicin 75 mg/m^2 plus paclitaxel 175 mg/m^2 or docetaxel 75 mg/m^2 every 3 weeks for at least 2 cycles. The primary endpoint was pathologic complete response （pCR）, which was defined as no residual invasive cancer, or only carcinoma in situ in both the excised breast and axillary lymph node, while relapse-free survival （RFS） and overall survival （OS） were secondary endpoints. Thirty-nine （90.7%） patients were at clinical stages II B-IIIC. Thirty-seven （86%） completed 4-6 cycles of preop- erative chemotherapy, and objective response rate （ORR） was 81.4% （35/43）. Forty-two patients un- derwent radical surgery subsequently. The pCR rate was 14.3% （6/42）. The most common adverse events in neoadjuvant chemotherapy were nausea/vomiting （88.4%, 38/43） and neutropenia （88.4%）. After a median follow-up period of 34.0 months, 3-year RFS and OS rate was 53.6% and 80.1%, respectively. All events of recurrence and death occurred in non-pCR patients, in whom the 3-year RFS and OS rates were 44.3% and 76.6%, respectively. This study suggest that neoadjuvant chemotherapy with epirubicin plus taxanes has a relatively low pCR rate and high early recurrence risk in locally ad- vanced TNBC, which indicates the necessity for more efficacious treatment. Further study is needed to validate these results.

A Highly Regioselective Deacetylation of Taxanes

A highly regioselective O-deacetylation of taxanes at C-5 position was accomplished by treatment with t-BuOK and a possible mechanism was proposed.

A New Abeotaxane Diterpenoid from the Seeds of Taxus mairei

A new abeotaxane was isolated from the seeds of Taxus mairei. Its structure was determined to be 2α, 5α, 13α-trihydroxy-7β, 10β-diacetoxy-2（3→20） abeotaxa-4（20）, 11-dien-9- one on the basis of 1D and 2D spectral analysis.

New Taxane Diterpenoids from Taxus yunnanensis

Three hitherto unknown taxane diterpenoids,namely baccatin Ⅷ(1),baccatin Ⅸ(2),and baccatin Ⅹ(3),along with 10 known analogues were isolated from an ethanolic extract of the twigs and leaves of Taxus yunnanensis.The new structures were characterized based on extensive spectroscopic analysis.Compounds 1 and 2 were tested for their in vitro cytotoxicity against five human tumor cell lines,and 1 exhibited inhibitory effects on HL-60 and MCF-7,with IC_(50) values of 3.44 and 9.67 μM,respectively.

NEW TAXANES FROM TAXUS CHINENSIS.2

Tow new taxane diterpenes were isolated from the leaves and stems of Taxus chinensis.Thcir structures were established as 2-deacctyl-5-decinnamatetaxagifine and taxagifinc Ⅲ on the basis of spectroscopic analysis.

TAXAYUNTIN A,B,C AND D----FOUR NEW TETRACYCLIC TAXANES FROM TAXUS YUNNANENSIS

Four new taxane diterpenoids were isolated from the bark of Taxus yunnanensis.Their structures were elucidated as the new skeleton with 5/7/6/4 membered rings by spectral analysis and 2D NMR shift correlation experiments.

YUNNANXOL AND YUNNANXAHINE——TWO NEW TETRACYCLIC TAXANE DITERPENOIDS FROM TAXUS YUNNANENSIS

Two new tetracyclic taxane diterpenoids----yunnanxol(1) and yunnanxamine(2)have been isolated from the bark of Taxus yunnanensis Cheng et L.K.Fu.Their structures have been established from the spectral data,mainly from MS,highfield ~1H NMR,~1H-~1H COSY, ^(13)C NMR,^(13)C-~1H COSY and ^(13)C-~1H COLOC spectroscopies.

TAXAYUNTIN,A NEW TETRACYCLIC TAXANE FROM THE LEAVES OF TAXUS YUNNANENSIS

A new skeleton taxane diterpene,taxayuntin,was isolated from the leaves and stems of Taxus yunnanensis.Its structure was determined by spectroscopic methods(MS,~1H NMR,^(13)C NMR, ~1H-~1H COSY,~1H-^(13)C COSY and ^(13)C-~1H COLOC)and X-ray diffraction.

抗Taxane的新机制

据美国BIOCOMPARE科技新闻网（2006／7／21）报道，斯坦福大学Stanley N．Cohen博士实验室的Chih·Jian Lih和其同事，研究人员利用一种可以随机改变哺乳动物细胞之基因表现的方法，以及可以检测改变的基因功能之筛选方法，确定出之前从未确定出的基因txr1。前列腺癌细胞中，这种基因表现的增加会导致患者对于taxane药物的抗性。Taxanes是一类广泛使用的化疗药物，商品名为docetaxel和paclitaxel。这类药物可以抑制微管降解和之后细胞分裂，以阻止癌细胞的生长。

Optic Nerve Metastasis from Breast Carcinoma after Treatment with Taxanes

Introduction: The incidence of ocular metastasis from Breast Carcinoma is only between 5% - 30%, mainly located in choroid, but the location in optic nerve is even more infrequent. We present a rare case that combined both locations sequentially in the same eye. Methods: Case report. Results: A 58-year-old woman with advanced breast cancer was referred with a choroidal metastasis in her right eye which responded well to systemic Taxol and Avastin. Afterwards, she developed an optic nerve metastasis in the same eye when she was under the treatment, so it was changed to Docetaxel. Unfortunately the patient didn’t respond to this treatment and died. Conclusions: Choroidal metastasis secondary to breast cancer generally responds well to radiotherapy. Even so, in cases that a great deterioration of visual acuity is expected after radiation, chemotherapy like taxanes is an alternative to preserve vision with complete tumor regression. Nevertheless, the presentation of a second metastasis in optic nerve can be indicative of inadequate treatment of metastatic disease or complication of the treatment, or both.

Two New Taxane Diterpenoids from Taxus Chinensis

Two new taxane diterpenoids, 2-deacetoxy-7,9-dideacetyltaxinine J (1) and 2-deacetoxytaxinine B (3), were isolated from the barks of Taxus chinensis. Their structures were elucidated by spectroscopic methods.

Methylated PLK2 is a prognostic biomarker in taxane-treated breast cancers

Background:In search of potential biomarkers of drug responsiveness the tumour suppressor PLK2 has been identified as a mediator of taxane sensitivity in some tumour types,based on its role of G2M checkpoint regulation.Objective:The current study set out to evaluate PLK2 methylation in breast cancer treated with neo-adjuvant chemotherapy including a taxane,as a biomarker of disease progression.Methods:Silencing of PLK2 in MCF-7 cells followed by taxane treatment was assessed using apoptotic readout for proof of principle.DNA was extracted from 64 cases of diagnostic surgical FFPE sections.Using pyrosequencing,levels of PLK2 promoter methylation were measured.Results:Silencing of PLK2 resulted in a significantly reduced apoptotic response following paclitaxel treatment(compared with scramble transfected controls).An association with higher levels of CpG island promoter methylation was seen for those cases with a progression-free survival(PFS)of less than 12 months.Kaplan-Meier analysis showed there was an association between overall survival(OS)and level of methylation(p=.06).Conclusions:Thus,based on data obtained from this pilot study,further larger studies evaluating the utility of PLK2 methylation as a potential predictive biomarker in breast cancer are warranted.

Adjuvant Taxanes in Breast Cancer: A Critical Re-appraisal

Purpose: Several studies have reported a positive impact for taxanes in adjuvant breast cancer (BC) treatment in terms of reduced recurrence and mortality. However the impact of the magnitude on overall survival (OS) remains partially controversial. Methods: We examined the impact of taxane-containing adjuvant therapy for patients with early BC on OS, based on the number of deaths and on the calculated number of patients who need to be treated with taxanes to avoid one death (NNT). We classified patients in three different groups according to whether taxanes were administered concurrently or sequentially, and whether all treatment arms had the same or different duration. Results: 1) Taxanes in combination therapy: 8258 patients (4373 with taxanes and 3885 without taxanes), with 723 OS events. Overall survival for taxane-treated patients was 92.7% versus 89.6% for patients not receiving taxanes. NNT was 33. 2) Sequential treatment of unequal duration in the treatment arms: 14,228 patients (7970 with taxanes and 6256 without). Overall survival in taxane-treated patients was 86% compared with 83.2% for patients not receiving taxanes. NNT was 44. 3) Sequential treatment and similar duration in treatment arms: 9511 women (5093 with taxanes and 4418 without). Overall survival in patients treated with taxanes was 87% versus 85% in patients not receiving taxanes. NNT was 50. When the results of all these trials were considered together, the NNT stands at 43 patients. Conclusion: Taxanes afford a modest increase in overall survival in BC patients regardless of how they are given. Translational trials may well help to improve patient selection in the future.

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity

7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag20 as catalyst and DMF as solvent. The catalyst could he quantitatively recovered by filtra- tion without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives （e.g., docetaxel and paclitaxel） to 7-epi-taxane derivatives （e.g., 7-epi-docetaxel and 7-epi-paclitaxel）. Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with ICs0 value as low as 15.9 nmol/L for 18.

Concurrent chemoradiotherapy comparison of taxanes and platinum versus 5-fluorouracil and platinum in nasopharyngeal carcinoma treatment

Background Nasopharyngeal carcinoma （NPC） is a squamous-cell carcinoma especially prevailing among the natives of southern China.The regimen of concurrent chemoradiotherapy （CCRT） that include platinum and 5-fluorouracil （5-FU）is considered to be the standard treatment for NPC.However,its clinical use is limited by its toxicity.Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment.Methods Medline,the Cochrane library,and the Chinese medical literature database were searched for eligible studies.Meta-analysis was performed using Review Manager （Version 5.2）.Results Six random controlled trials （RCTs） including 514 patients met our criteria.Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission （CR） and less incidence rate in adverse reactions such as gastrointestinal impairment grades Ⅲll-Ⅳ,liver and kidney impairment grades Ⅰ-Ⅱ,and radiodermatitis grades Ⅲ-Ⅳ versus the conventional regimen of CCRT with 5-FU and platinum,while the long-term effectiveness rate of overall survival,Iocoregional failure-free survival,or distant metastasis failure-free survival between the two groups was therapeutic equivalence.Conclusions The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT.However,we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare,analyze,and confirm the findings.