67 Paclitaxel poliglumex药理药效研究 动物模型

O RIGINAL A RTICLEPaclitaxel Poliglumex(PPX-Xyotax)and Concurrent Radiation for Esophageal and Gastric CancerA Phase I StudyTom Dipetrillo,MD,*Luka Milas,MD,†Devon Evans,MD,*Paul Akerman,MD,*Thomas Ng,MD,* Tom Miner,MD,*Dennis Cruff,MD,*Bharti Chauhan,MD,*David Iannitti,MD,*David Harrington,MD,*and Howard Safran,MD*Objectives:To determine the maximal tolerated dose(MTD)and dose limiting toxicities of poly(L-glutamic acid)-paclitaxel(PPX)and con-current radiation(PPX/RT)for patients with esophageal and gastric cancer.Methods:Patients with esophageal or gastric cancer receiving chemo-radiation for loco-regional,adjuvant,or palliative intent were eligible. The initial dose of PPX was40mg/m2/wk,for6weeks with50.4Gy radiation.Dose levels were increased in increments of10mg/m2/wk of PPX.Results:Twenty-one patients were enrolled over5dose levels.Sixteen patients had esophageal cancer and5had gastric cancer.Twelve patients received PPX/RT as definitive loco-regional therapy,4patients had undergone resection and received adjuvant PPX/RT,and5patients had metastatic disease and received PPX/RT for palliation of dyspha-gia.Dose limiting toxicities of gastritis,esophagitis,neutropenia,and dehydration developed in3of4patients treated at the80mg/m2dose level.Four of12patients(33%)with loco-regional disease had a complete clinical response.Conclusions:The maximally tolerated dose of PPX with concurrent radiotherapy is70mg/m2/wk for patients with esophageal and gastric cancer.Key Words:paclitaxel polyglumex,concurrent chemoradiation, esophageal cancer,gastric cancer,macromolecule drug conjugate (Am J Clin Oncol2006;29:376–379)P PX is a drug conjugate that links paclitaxel to a biodegrad-able polymer,poly-L-glutamic acid.1Preclinically,poly(L-glutamic acid)-paclitaxel(PPX)has demonstrated tumor tissue radiation enhancement factors from4.0to8.0compared with1.5 to 2.0for paclitaxel.2PPXs macromolecular structure may underlie its improved radiation enhancement.PPX has a molec-ular weight of40,000compared with854for paclitaxel.3Solid tumors are more permeable to macromolecules thannormal tissue because of altered capillary endothelium.4Further-more,macromolecules persist longer in tumor tissue because ofthe relative decrease in lymphatics compared with non-neoplas-tic tissue.5Radiation increases the vascular permeability of solidtumors.6,7Local tumor irradiation in tumor cell lines increasesvascular permeability and increases PPX uptake.2Tumor se-creted vascular endothelial growth factor also increases vascularpermeability.8The combination of PPX and radiation in theovarian Oca-1carcinoma implanted in C3Hf/Kam mice pro-duced a significantly greater tumor growth delay than treatmentwith radiation and paclitaxel when both drugs were given at anequivalent paclitaxel dose(enhancement factors of4.44versus1.50).2These preclinicalfindings support the hypothesis that thesupra-additive effect of combined PPX/RT is because of themodulation of the enhanced permeability and retention effect ofmacromolecules by radiation.Paclitaxel is an important radiation sensitizer in uppergastrointestinal malignancies.9–14We initiated a phase I trial ofPPX/RT for patients with esophageal and gastric cancer.This isthefirst report of a clinical study utilizing a poly L-glutamic acidmacromolecule as a radiation sensitizer in human malignancies.MATERIALS AND METHODS EligibiltyPatients with a histologically confirmed diagnosis of esoph-ageal adenocarcinoma or squamous cell carcinoma,or gastric ade-nocarcinoma were enrolled between January2004and May2005.PPX/RT could be administered as definitive loco-regional oradjuvant therapy.Patients with metastatic disease with dyspha-gia were also eligible.Required laboratory parameters includedabsolute neutrophil countϾ1,500␮L hemoglobinϾ10g/dL, plateletsϾ100,000␮L,creatinineϽ1.5mg/dL,bilirubinϽ1.5 mg/dL,alanine aminotransferase,and alkaline phosphatase Ͻ2.5ϫupper limit of normal,and calciumϽ12mg/dL.Patients with previous irradiation,Eastern Cooperative Oncology Group(ECOG)performance statusϾ1,life expectancyϽ12weeks,tracheobronchial invasion,tracheoesophagealfistula,unstableFrom The*Brown University Oncology Group,Providence,RI;and the †Department of Experimental Radiation Oncology,The University of Texas M.D.Anderson Cancer Center,Houston TX.Reprints:Devon Evans,MD,Brown University,Department of Hematology/ Oncology,164Summit Avenue,Providence,RI02906.E-mail:devans@ .Copyright©2006by Lippincott Williams&WilkinsISSN:0277-3732/06/2904-0376DOI:10.1097/01.coc.0000224494.07907.4ecardiac disease within6months,active infection,brain metas-tasis,laryngeal or phrenic nerve paralysis,unstable neurologic symptoms,sensory or motor neuropathy greater than grade1,or other concurrent malignancy,were excluded.A complete his-tory and physical examination were performed on all patients before treatment.Height,weight,performance status,and tumor stage were recorded.Required staging studies included a com-puted tomography(CT)scan of the chest,abdomen,and pelvis. Pre-and post-treatment endoscopies were required only in pa-tients with loco-regional disease.The study was approved by the institutional review boards of all participating hospitals and Brown University.All patients gave written informed consent according to federal and institutional guidelines. ChemotherapyPPX was administered as a10-minute infusion before radiotherapy on days1,8,15,22,29,36on an outpatient basis. Patients were treated with PPX according to a dose escalation scheme,with patients enrolled in cohorts of3at each dose level. The initial dose level was40mg/m2/wk in3patients,and was increased in increments of10mg/m2/wk in the next patient cohort if no patients had a dose limiting toxicity(DLT).All toxicities were graded according to the NCI Common Toxicity Criteria,Version3.Dose limiting toxicities were defined as grade3esophagitis,enteritis or gastritis,grade3nausea(despite maximal antinausea treatment)or dehydration,any other grade3 or4nonhematologic toxicity,and grade4neutropenia or throm-bocytopenia lasting more than1week.Toxicities were consid-ered dose limiting only if they resulted from toxicity of chemo-radiation,and not from disease progression.If one or2patients experienced a DLT,then3additional patients were enrolled at the same dose level.If no more than2patients total experienced a DLT at that dose level,than the dose was escalated for the next patient cohort.IfϾ2patients had a DLT,then the dose was de-escalated to the next dose level,and3additional patients enrolled.The MTD was defined as the dose at which no more than2of6patients have a DLT.RadiotherapyPatients received radiation concurrently with chemother-apy to a total dose of50.4Gy,administered at1.8Gy/d,for a total of28days(5days/wk)using aՆ10-MV linear accelerator. Three-dimensional conformal radiation was used to treat all patients.For esophageal and gastric cancers extending to the esophagus,the treatmentfields extended5cm beyond the superior and inferior borders,and2cm beyond the lateral margins.For gastric tumors confined to the stomach,the radia-tionfields encompassed the primary tumor and draining lymph nodes with a2to3cm margin in all directions.The right lateral margins included the portal,hepatic,and common bile duct as well as the head of the pancreas.Postsurgical patients receiveda radiation dose of45Gy delivered in25fractions(1.8Gy/d)for5.5weeks followed by a cone down after45Gy to encompass gross or microscopic disease with a margin of1to1.5cm,for a total dose of50.4Gy.ResponseResponse to treatment was assessed by pre-and posttreat-ment upper endoscopy.Only patients with loco-regional disease had disease assessable for response.A clinical complete re-sponse was defined as no tumor visible on follow-up endoscopy and no tumor on posttreatment biopsy.RESULTSPatient CharacteristicsTwenty-one patients(all Caucasian)were enrolled in this study.Patient characteristics are listed in Table1.Sixteen pa-tients had esophageal cancers,and5patients had gastric cancers extending to the gastroesophageal junction.Twenty patients had adenocarcinomas,and1patient had squamous cell carcinoma. Twelve patients received PPX/RT to treat loco-regional disease. Four patients received PPX/RT for adjuvant therapy after resec-tion,and5patients with metastatic disease at study entry were treated with PPX/RT for local control and symptom palliation. Seven patients had been treated previously with chemotherapy. ToxicityPatients received PPX/RT over5dose levels(see Table2). At the80mg/m2dose level,3of4patients had dose limiting toxicities including grade3esophagitis/gastritis(nϭ2),grade3 dehydration(nϭ1),and grade4neutropenia(nϭ1).One of6 patients at the70mg/m2dose level had grade3esophagitis. There were no grade3or4toxicities at dose levels below PPX 70mg/m2/wk.Dose limiting toxicities did not correlate with either disease site(gastric versus esophageal)or previous che-motherapy treatment.Except for the4patients who experienced a dose limiting toxicity,all patients completed the full6weeks of concurrent chemoradiation.Acute toxicities during chemoradiation are listed in Table3. Multiple toxicities in a single patient are scored as separate events.Esophagitis and dehydration were the most common grade3/4toxicities.One grade2hypersensitivity reaction(urti-caria)was noted among the21patients treated.The patient was TABLE1.Patient CharacteristicsNo.patients enrolled21 SexMale18 Female3 Tumor typeEsophageal16 Gastric5 PathologyAdenocarcinoma20 Squamous cell1 Treatment indicationLoco-regional12 Adjuvant4 Palliation(metastatic)5 Prior chemotherapy7 Median age in years(range)63(41–91)American Journal of Clinical Oncology•Volume29,Number4,August2006PPX-Xyotax and Radiation for Esophagogastric Cancersuccessfully retreated without further hypersensitivity reaction following dexamethasone and diphenhydramine premedication. No alopecia was observed in this study.ResponseTwelve patients had loco-regional disease and were as-sessable for response on posttreatment endoscopy.Four of12 patients(33%)had complete clinical response.An additional7 patients hadϾ50%tumor reduction as assessed by posttreat-ment endoscopy.Loco-regional activity was seen in patients who developed systemic metastases during treatment.DISCUSSIONPaclitaxel is a commonly used radiation sensitizer in multiple tumor types.9–18Paclitaxel synchronizes cells in G2/M, the most radiosensitive phase of the cell cycle,by enhancing microtubule assembly and preventing microtubule depolymer-ization.19–21Paclitaxel has the exceptional property of killing tumor cells in the absence of wild-type p53function in vitro.22 We demonstrated that p53gene mutations are not predictors of unfavorable response to paclitaxel/RT.23Paclitaxel radiosensi-tizes small bowel progenitor cells less than tumor cells poten-tially increasing the therapeutic index of paclitaxel radiosensi-tization in upper gastrointestinal cancers.24PPX is a drug conjugate that links paclitaxel to a biode-gradable polymer,poly-L-glutamic acid.The resulting macro-molecule has several beneficial properties.It is water-soluble, eliminating the need for Cremophor EL and thus reducing the risk of hypersensitivity reactions,and can be given as a10-minute infusion.The hyperpermeable angiogenic vasculature and suppressed lymphatic clearance of tumors facilitate PPX retention within the tumor space,resulting in higher intratumor drug concentrations over prolonged periods.This effect has been described as the enhanced permeability and retention effect(EPR).PPX is absorbed by tumor cells by endocytosis,bypassing the MDR pathway that commonly causes chemotherapy drug resistance.25,26PPX has been evaluated in a phase III trial in patients with performance status2advanced nonsmall cell lung cancer.This study demonstrated a similar response and sur-vival of PPX and carboplatin as compared with paclitaxel and carboplatin.27Radiation increases the vascular permeability of solid tumors.6,7The modulation of the EPR of macromolecules by radiation may underlie the striking preclinical enhancement of radiation and PPX.2This is thefirst clinical trial of PPX and concurrent RT.The maximum tolerated dose of PPX is70 mg/m2/wk with50.4Gy radiation for patients with esophageal and gastric cancer.The toxicities observed in this study of esophagitis,gastritis,and nausea were attributable to PPX in-duced RT enhancement.Substantial preliminary activity was demonstrated in this phase I study with one-third of patients undergoing a complete clinical response to PPX/RT alone.Loco-regional activity was demonstrated in some patients developing systemic progression illustrating that PPXs most important effect was as a radiation sensitizer.We have initiated a phase I study evaluating PPX, cisplatin,and concurrent radiation for patients with esophageal and gastric cancer.Based on the strong preclinical data and the promising preliminary results with PPX/RT,further evaluation of PPX radiosensitization in other human tumors is warranted.REFERENCES1.Singer JW,Baker B,de Vries P,et al.Poly-(L)-glutamic acid–paclitaxel(CT-2103)͓XYOTAXt͔,a biodegradable polymeric drug conjugate.Adv Exp Med Biol.2003;519:81–99.2.Chun Li,Shi Ke,Qing-Ping Wu,et al.Tumor irradiation enhances thetumor-specific distribution of poly(l-glutamic acid)-conjugated pacli-taxel and its antitumor efficacy.Clin Cancer Res.2000;6:2829–2834.3.Li C,Yu DF,Newman RA,et plete regression of well-estab-lished tumors using a novel water-soluble poly(l-glutamic acid)-pacli-taxel conjugate.Cancer Res.1988;58:2404–2409.4.Gerlowski LE,Jain RK.Microvascular permeability of normal andneoplastic tissue.Microvasc Res.1986;31:288–305.5.Maeda H,Matsumura Y.Tumoritropic and lymphotropic principles ofmacromolecular drugs.Crit Rev Ther Drug Carrier Syst.1989;6:193–210.6.Baker DG,Krochak RJ.The response of the microvascular system 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ANC40300005040000604000070601008042211TABLE3.ToxicityՆGrade2No.Patients(n؍21)Grade2Grade3Grade4NonhematologicalEsophagitis/gastritis530Nausea/vomiting310Anorexia400Dehydration720Fatigue/weakness610Infection200Hypersensitivity100HematologicalNeutropenia001Thrombocytopenia110Dipetrillo et al American Journal of Clinical Oncology•Volume29,Number4,August200611.Safran H,Gaissert H,Akerman P,et al.Paclitaxel,cisplatin andconcurrent radiation for esophageal cancer.Cancer Invest.2001;1:1–7.12.Safran H,Moore T,Iannitti D,et al.Paclitaxel and concurrent radiationfor locally advanced pancreatic cancer.Int J Radiat Oncol Biol Phys.2001;49:1275–1279.13.Ajani JA,Mansfield PF,Crane CH,et al.Paclitaxel-based chemoradio-therapy in localized gastric carcinoma:degree of pathologic response and not clinical parameters dictated patient outcome.J Clin Oncol.2005;23:1237–1244.14.Brenner B,Ilson DH,Minsky BD,et al.Phase I trial of combined-modality therapy for localized esophageal cancer:escalating doses of 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CJ,Socinski MA,Ross H,et al.Paclitaxel poliglumex(PPX)/carboplatin vs paclitaxel/carboplatin for the treatment of PS2 patients with chemotherapy-naı¨ve advanced non-small cell lung can-cer(NSCLC):a phase III study.Proc Am Soc Clin Oncol.2005;LBA: 7011.American Journal of Clinical Oncology•Volume29,Number4,August2006PPX-Xyotax and Radiation for Esophagogastric Cancer。