Update on Combined-Modality Treatment Options for Pancreatic Cancer

ABSTRACT: Cancer of the pancreas remains a formidable challenge in oncology.This malignancy ranks as the fourth leading cause of cancer deathin the United States in 2003, with an estimated 30,700 new cases to bediagnosed and 30,000 deaths. Although gains have been achieved inthe clinical management of these patients, this malignancy is rarelycurable. Long-term survival is limited to patients undergoing resection.For patients with localized but unresectable malignancy, radiationtherapy combined with fluorouracil, gemcitabine (Gemzar), orpaclitaxel has shown modest improvements in survival and symptompalliation. However, there has been significant progress in the diagnosticevaluation of pancreatic cancer patients, which has aided cliniciansin caring for these patients and in selecting therapies. The use ofcomputed tomography, endoscopic ultrasonography, and laparoscopytechniques will be discussed. Newer techniques of radiation therapy,such as intraoperative electron-beam radiation therapy and threedimensionalconformal radiation therapy, with the integration of newbiologically targeted agents may provide new avenues of research andprogress in this disease.Cancer of the pancreas is thefourth leading cause of cancerdeath in the United States.[1]In 2003, an estimated 30,700 new patientsand approximately 30,000deaths are expected to occur from thisdisease.[2] Because the etiology ofthe disease is poorly understood andclinical presentation is late in its naturalhistory, cure remains elusive. Forthe 10% to 15% of patients undergoingresection, the 5-year survival ofpatients with "favorable" localizeddisease (ie, no lymph node metastasesand disease confined to the pancreaswithout capsular invasion) approaches18% to 24%.[3] For patients with advancedor metastatic disease, there areonly anecdotal reports of survivors beyond5 years. For all stages combined,the 5-year survival rate is 4%.[4] Becauseof these poor survival results,adjuvant and neoadjuvant treatmentstrategies have been investigated. Newcombinations of cytotoxic chemotherapyand targeted agents, and improvementsin radiation therapy such asthree-dimensional (3D) conformal radiation,may improve survival in patientswith locally advanced pancreaticcancer. This review will highlight someof these developments.Palliation of symptoms is a majorgoal of therapy for patients with locallyadvanced or metastatic pancreaticcancer. Gastric outlet or biliaryobstruction and pain are frequent andsignificant clinical problems, and requirejudicious selection of surgical,medical, and endoscopic or radiologicintervention. These procedures havebeen helpful in palliation and improvingpatient quality of life.[5,6]When resection is feasible, longtermsurvival may result.[3,7] For pa-tientswith locally advanced unresectabletumors, median survival is 8 to 13months. The National Cancer Instituterecommends that patients with any stageof pancreatic cancer be considered forenrollment in a clinical trial.Treatments forResectable TumorsAdjuvant Therapy
At present, surgery offers theonly therapeutic means of cure forpancreatic cancer. Only 5% to 25% ofpatients present with tumors amenableto resection. Patients who undergoresection for localized pancreaticcarcinoma have a long-term survivalrate of approximately 20% and mediansurvival of 13 to 20 months.[8]Favorable subsets include patientswith resected tumors measuring lessthan 3 cm, no lymph node metastases,and microscopically negative surgicalmargins.

The Gastrointestinal Tumor StudyGroup (GITSG) evaluated the potentialvalue of adjuvant therapy for patientswith pancreatic cancer (Table1). In one of the GITSG's earlier trials,patients with resected tumorswho received adjuvant combinationchemoradiation with fluorouracil(5-FU) and split-course radiation of40 Gy in 20 fractions had a significantsurvival advantage, with a mediansurvival of 21 months comparedwith 11 months for patients not receivingradiation therapy and chemotherapyafter resection. These findingswere confirmed in a follow-up registrytrial which found that combinedadjuvant radiation/5-FU therapy yieldeda 2-year actuarial survival of 43%(95% confidence interval [CI] = 25%-63%) in those patients receiving theadjuvant therapy, compared to 18%(95% CI = 5%-36%) in those whounderwent surgical resection alone.[9]The European Organization forResearch and Treatment of Cancer(EORTC) was unable to reproducethese positive results in a randomizedtrial of 218 patients with pancreas orperiampullary cancers. A subset analysisof patients with primary tumorsof the pancreas (114 patients) did,however, show a trend toward improved2-year (median) and 5-year(overall) survival.[10] In this phaseIII trial, resected patients received eithersplit-course irradiation (40 Gy)with concurrent 5-FU or were observed.Median survival was 19months in observed patients comparedwith 24.5 months in those whoreceived postoperative treatment(P = .208), with an estimated 2-yearsurvival of 41% and 51%, respectively.Subset analysis of pancreatic cancerpatients, however, showed anestimated 2-year survival of 26% forthe observation patients compared to34% for those receiving the adjuvanttreatment (P = .099). Patients withperiampullary tumors had a muchhigher estimated 2-year survival of63% to 67%. These investigators concludedthat for patients undergoingsurgical resection, the benefit of adjuvanttherapy was limited and did notjustify its routine use.A second European trial has examinedvarious adjuvant treatmentapproaches, including 40-Gy splitcourseradiation therapy with concurrentand maintenance chemotherapyas well as chemotherapy alone.[11]The European Study Group for PancreaticCancer (ESPAC-1) phase IIItrial showed no survival advantagefor postoperative irradiation and5-FU chemotherapy vs no furthertreatment after surgery. However, atherapeutic benefit was seen for patientsreceiving adjuvant chemotherapyof 5-FU and leucovorin only. TheESPAC-3 trial is defining the role ofadjuvant chemotherapy following curativeresection of pancreatic ductaladenocarcinoma. In this study, 5-FUplus folinic acid for 24 weeks will becompared with gemcitabine (Gemzar)for 24 weeks vs no chemotherapy followingsurgery. The aim is to recruit330 patients in each arm for a total of990 patients. Enrollment is ongoing.Given conflicting results from variousstudies, the exact role of postoperativeradiation therapy is uncertainat present. However, considering thevery poor outcomes with surgeryalone (15% 5-year survival) and theencouraging results from well-designedand controlled studies from singleinstitutions and cooperative groupsusing contemporary techniques, thereis a rationale to support adjuvant therapywith radiation therapy and 5-FU,as for other gastrointestinal carcinomas.The Radiation Therapy OncologyGroup, in conjunction with the GIIntergroup, has recently completed aphase III trial examining whether gemcitabineimproves survival over 5-FUas maintenance therapy for patientswith resected pancreatic cancer receivingradiation therapy and concurrent5-FU.Neoadjuvant Therapy
In addition to postoperative treatmentstrategies, there has also beeninterest in the use of preoperative radiationtherapy and chemotherapy forpatients with resectable pancreaticcancer. In one institutional analysisof 132 patients who had received pre-operative chemoradiation (5-FU,paclitaxel, or gemcitabine with either45 to 50 Gy radiation at 1.8 Gy/fractionor 30 Gy at 3.0 Gy/fraction) beforepancreaticoduodenectomy foradenocarcinoma of the pancreas head,a median survival of 21 months wasfound for all chemoradiation combinations.[12] In this study, superiorsurvival was observed for women(P = .04) or those with no evidence oflymph node metastasis (P = .03). Interestingly,there was no difference inmedian survival between standardfractionationchemoradiotherapy(50.4 Gy for 5.5 weeks) and rapidfractionationradiation therapy (30 Gyfor 2 weeks).In another analysis of neoadjuvantchemoradiation therapy, patients whoreceived preoperative treatment of5-FU (with or without mitomycin[Mutamycin] or gemcitabine) plus radiationtherapy (50.4 Gy) demonstrateda median overall survival of 34months (range: 8-152 months) comparedwith 8 months (range: 1-14months) for those who could not undergosurgery (P = .005).[13] Theresults of these studies have suggestedspecific advantages for preoperativevs postoperative radiation therapyand chemotherapy. Some of these potentialadvantages include no delay ininitiation of radiation therapy (previousstudies showed that 25% of patientsrequired a 10-week delay forpostoperative recovery), reduced riskof tumor cut-through, which is importantgiven the high rates of retroperitonealmargin involvement of thesemalignancies, and avoidance of a laparotomyin patients who would not bepotentially curative given the frequentdevelopment of detectable metastaseson restaging evaluation after radiationtherapy and chemotherapy.Treatment of UnresectableTumorsIn the past, 45% of patients withnewly diagnosed pancreatic cancerpresented with locally advanced disease.More recent data confirming thisfigure are lacking, and it is possiblethat more advanced staging tools showmetastatic disease early in the courseof a patient's illness, thus decreasingthis percentage. In general, a tumor isconsidered unresectable if it has oneof the following features: (1) extensiveperipancreatic lymph node involvement,(2) encasement of thesuperior mesenteric vein/portal veinconfluence, (3) direct involvement ofthe superior mesenteric artery, inferiorvena cava, aorta, or celiac axis, or(4) distant metastases. Through a seriesof randomized studies publishedin the 1980s, chemoradiotherapy hasbecome the accepted standard of carefor locally advanced and nonmetastaticcarcinoma.Radiation Therapyand Chemotherapy
A Mayo Clinic study and a series ofGITSG studies performed primarily inthe 1980s demonstrated that externalbeamradiation therapy (EBRT) combinedwith 5-FU was superior to eitherradiation or chemotherapy treatmentalone (Table 2).[14-17] In the MayoClinic study, 64 patients with unresectableadenocarcinoma of the pancreaswere randomized to 40 Gy radiationwith either concurrent 5-FU or concurrentplacebo. The median survival forthe chemotherapy patients was 10.4months, compared with only 6.3 monthsfor those receiving placebo.In a similar GITSG trial that evaluated194 patients with surgically confirmedunresectable and nonmetastaticdisease, survival was improved whena combined treatment of either 40 Gyfor 6 weeks or 60 Gy for 10 weeksplus 5-FU (2 to 3 cycles with maintenance5-FU after radiation) was usedas compared with radiation therapyalone using 60 Gy.[15] Combinedmodalitytherapy using 60 Gy showedthe greatest benefit compared withcombined chemotherapy with a40-Gy dose or therapy with 60 Gyradiation alone; the 1-year survivalwas 10% for radiation alone, 35% for40 Gy combined therapy, and 46%for 60 Gy combined therapy.Follow-up GITSG studies wereconducted to further clarify the benefitof different chemotherapeutic regimenswith radiation therapy in thesepatients. One trial was designed tocompare radiation plus either 5-FU ordoxorubicin. In this trial, 157 patientswere randomized to either 60 Gy splitcourseEBRT with concurrent andmaintenance 5-FU, or 40 Gy continuous-course radiation with concurrentdoxorubicin and maintenance doxorubicinplus 5-FU. No survival advantagewas seen with either treatmentarm; however, those patients receivingdoxorubicin experienced significantlyhigher rates of treatment-relatedtoxicity (P < .05).[16]Another study compared the combinedtreatment of streptozocin(Zanosar)/mitomycin/5-FU (SMF)chemotherapy alone to 5-FU chemotherapyplus radiation followed byadjuvant SMF chemotherapy. Thistrial enrolled 48 patients random-ized to chemotherapy alone orchemoradiation. The 1-year survivalfor patients receiving chemoradiationwas 41% compared with 19% of patientsreceiving chemotherapyalone.[17]

In these trials, it was shown thatthe combination of radiation therapyand chemotherapy was superior to radiation(1-year survival, 40% vs 10%)or chemotherapy alone (1-year survival,41% vs 19%). However, whenthe Eastern Cooperative OncologyGroup (ECOG) performed a similarevaluation in 91 patients with locallyunresectable adenocarcinoma of thepancreas, no survival benefit wasshown with the use of concurrent bolus5-FU during week 1 with 40 Gyradiation compared to 5-FU chemotherapyalone.[18] The median survivalwas 8.3 months with thecombined treatment vs 8.2 monthsfollowing treatment with 5-FU alone.The 1-year survival was 26% for patientsreceiving combination therapyand 32% for those receiving 5-FU. Inthis study, no patients received maintenancechemotherapy.With the exception of the ECOGstudy, conventional external-beam radiationcombined with 5-FU appearsto provide some survival benefit overmonotherapy with radiation therapyor chemotherapy for patientswith locally advanced unresectablepancreatic tumors. As a result, combined-modality therapy with 5-FUand external-beam radiation hasbecome a frequently used treatment.While multimodality treatmentwith 5-FU has shown modest benefit,recent investigative efforts havemoved to evaluation of gemcitabinecombinations with radiation therapy.These studies have been prompted asa result of phase III trials showingefficacy of gemcitabine in the treatmentof patients with metastaticpancreatic cancer.[19] In a large multicenterrandomized trial of patientswith locally advanced or metastaticdisease, clinical benefit and mediansurvival were significantly improvedwith the use of gemcitabine as comparedto treatment with 5-FU (5.65months vs 4.41 months). One-yearsurvival was 18% with gemcitabineand 2% with 5-FU (P = .003); however, survival was not extended beyond19 months.In an attempt to further improvethese results, ECOG performed aphase III trial (E2297) of gemcitabinein combination with 5-FU vs gemcitabinealone, no significant survivalbenefit was observed between the single-agent or combination therapies.[20] On the other hand, a smallinstitutional phase II study evaluatingweekly gemcitabine (1,000 mg/m²)with 5-FU (2,000 mg/m²) in 23 patientsfor 3 consecutive weeks followedby 1 week without treatmentuntil tumor progression occurred suggeststhat the gemcitabine/5-FU combinationmay improve 1-year survivaland median survival.[21] As comparedwith prior results with gemcitabinealone,[20] the combinationtherapy demonstrated a 1-year survivalrate of 30% (vs 18%) and amedian survival time of 8.3 months(vs 5.65 months). Clearly, these phaseII results in the metastatic setting needto be evaluated in a phase III trial toknow whether there is true benefit ofthe combination.The Cancer and Leukemia Group B(CALGB) has released early phase IIresults of its chemoradiation trial inwhich gemcitabine was used as a radiationsensitizing agent at 40 mg/m²twice weekly in combination with50.4 Gy radiation to the upper abdomen.With 38 evaluable patients, thestudy has concluded that toxicity ismanageable and median survival is encouragingwith chemoradiation, especiallyfor patients with a performancestatus of 0, where median survival was13.7 months as compared with 7.8months for those with a performancestatus of 1 or 2.[22] The follow-upstudy in CALGB is evaluating weeklygemcitabine combined with infusional5-FU during radiation therapy.Paclitaxel has also been investigatedin this setting due to its enhancedradiosensitizing effects inpreclinical studies. A phase I study atBrown University found the maximumtolerated dose of weekly paclitaxelto be 50 mg/m² when given with50 Gy of EBRT. This combinationyielded a 31% response rate among13 evaluable patients. In a follow-upphase II study, also at Brown University,this same dosing combinationyielded a 26% response rate, and a1-year survival rate of 30%.[23]Potential Surgical ResectionAfter Chemoradiation of LocallyAdvanced Pancreatic Cancer
Despite improvements in survivalwith chemoradiation, surgery remainsthe only potentially curative treatmentfor pancreatic cancer. Chemoradiationhas been employed in an effort topromote tumor regression and facilitateresection for patients with locallyadvanced tumors. Investigators fromNew England Deaconess Hospitaltreated 16 patients with unresectabletumors with preoperative 5-FU chemotherapyfollowed by 45 Gy ofEBRT and infusional 5-FU. Two ofthe patients (13%) were able to undergoresection following treatment.[24] Similar results were foundin a Duke University study in whichtwo patients (8%) were able to beresected after first being treated with45 Gy of EBRT and 5-FU with orwithout cisplatin or mitomycin.[25]A phase I dose-ranging study oftwice-weekly gemcitabine (10 mg/m²to maximum tolerated dose of approximately50 mg/m²) in combination withEBRT administered to 21 patients withadvanced adenocarcinoma of the pancreasfound that treatment enabled surgicalresection in three patients whohad previously unresectable tumors.[26] In a phase II study, weeklygemcitabine (1,000 mg/m²) was givenduring an induction phase of 7 weeks,followed by a combination of weeklygemcitabine (400 mg/m²) with 50.4 Gyradiation in 28 fractions in those whohad evidence of benefit from initialchemotherapy. Three patients underwentsurgical resection. Results showan overall median survival of 8 months(all groups combined). Interestingly, atthe time of publication, the median survivalfor the chemoradiation group hadnot yet been reached.[27]A retrospective analysis of patientswith locally advanced unresectablepancreatic cancer treated concurrentlywith weekly gemcitabine (250 to500 mg/m²) and radiation therapy (30to 33 Gy in 10 to 11 fractions over 2weeks) showed a median survival of11 months with 37 of 51 patients even-tually progressing.[28] While six patientswere later able to undergopancreaticoduodenectomy, the combinationtreatment was difficult to administersafely.Clearly, EBRT with chemotherapyoffers survival benefit as well as palliationof pain associated with the tumor.In the United States, combined-modalitytherapy has been adopted as thestandard treatment for patients with locallyadvanced pancreatic cancer. Whilethese combined treatments increase mediansurvival for patients with locallyadvanced carcinoma, treatment resultingin long-term survival is rare. As aresult, there have been renewed effortsto enhance patient outcomes and longtermsurvival by improving patient selectionthrough better staging of thedisease, and to offer treatments withpalliative benefits.Palliative Benefits FromChemoradiationDespite improvements in shorttermsurvival with therapy, patientswith locally advanced pancreatic cancerwill ultimately die of their disease.It is for this reason that treatmentswith palliative benefits that can improvequality of life remain an importantpriority in the managementof this disease. Unfortunately, improvementsin pain, anorexia, or fatigueare not well documented inmany of the studies. Pain relief hasbeen documented in some of the largerstudies, including one using intraoperativeelectron-beam radiationtherapy where relief was obtained in50% to 80% of patients.[29] External-beam radiation therapy with orwithout chemotherapy has also beenassociated with pain relief in 35% to65% of patients.[15,29,30] A few otherstudies have reported more subtleimprovements in performance statusand anorexic symptoms.[29-31]Diagnostic Tools andPatient SelectionCurrently available tools for thediagnosis and staging of pancreaticcancer patients include helicalcomputed tomography (CT) scans,endoscopic ultrasonography, MRIs,PET scans, and laparoscopy and washings.These imaging techniques haveaided physicians in characterizing thetumor site, determining the feasibilityof resection, and identifying the absenceor presence of metastasis. Afterappropriate staging and definition ofextent of disease, patients can then becounseled regarding available therapiesand ongoing clinical trials.Computed Tomography
Computed tomography scanning ofthe abdomen is the most commonlyused tool for diagnosis and staging.Newer-generation and higher-speedmachines now provide contrast enhancementand thin-section imaging.[32] As such, motion-freehigh-resolution images, including 3Dreconstruction of the pancreas, areavailable to define resectability of thelesion. A tumor may be resected ifthere is no extrapancreatic involvement(eg, no extensive parapancreaticlymph or distant involvement), noencasement or occlusion of the superiormesenteric vein (SMV) or SMV-portal vein confluence, and no directinvolvement of the superior mesentericartery, inferior vena cava, aorta,or celiac axis.A recent study assessing the resectabilityof pancreatic tumors preoperatively using CT scanning verified theaccuracy of CT scanning by findingthat, with the above criteria, most tumors(> 90%) considered unresectableby CT scanning were alsoconsidered unresectable at laparotomy.[33] Similarly, a second analysisconcluded that the determination ofresectability of a pancreatic carcinomawas best done with dual-phasehelical CT. The analysis further suggestedthat for improved accuracy ofdiagnosing lymph node involvementby pancreatic cancer, endosonographywith fine-needle aspiration shouldbe used; this is especially true in patientswith suspected carcinoma, eventhose with negative biopsy results.[34]Combined CT/PET scan imagingis further enhancing the ability to defineextent of disease. MRI scans arealso being employed to aid in evaluationof the extent of pancreatic cancer.Newer imaging contrast agentsmay be helpful in detecting the presenceof metastases, even in smalllymph nodes. Ongoing improvementsin all of these technologies shouldcontinue to refine the ability to stagethis malignancy.Endoscopic Ultrasound
Endoscopic ultrasonography hasproven to be useful in further char-acterizing the extent of the localdisease.[35] This procedure allowsfine-needle biopsy of the pancreaticneoplasm and regional nodes, allowingfor diagnosis and staging withoutexploratory surgery while decreasingthe potential for tumor seeding.[36]The procedure is often performed atthe time of an endoscopic retrogradecholangiopancreatography for the assessmentof pancreatic neoplasms.[37]

Staging Laparoscopy
Staging laparoscopy allows directvisualization of the liver, peritoneum,and omentum, and can identify 1- to2-mm metastatic nodules in patientswith potentially resectable or locallyadvanced disease. If metastatic diseaseis encountered, laparotomy canbe avoided. In one study of 114 patientswith no evidence of metastasisby CT, laparoscopy was able to identifymetastatic disease in 27 patients(~24%).[38] Interestingly, a smallstudy of 64 patients designed to compareendoscopic sonography with helicalCT for the identification andstaging of pancreatic ductal adenocarcinomafound that endoscopicsonography was more accurate thanhelical CT (95.3% vs 89.1%). Forthose who underwent laparotomy(n = 43), however, helical CT moreaccurately predicted resectability thandid endosonography (86% vs 81.4%).With the advent of new laparoscopichand-access devices, a surgeonis now able to place a hand in theabdomen and perform functions previouslypossible only during open surgery.[40] Peritoneal washings may becombined with laparoscopy to assessthe presence or absence of malignantcells in peritoneal fluid. For patientswithout visible metastases at laparoscopybut cytologic involvement inperitoneal washings, survival rates aresimilar to patients with macroscopicmetastatic disease.[39]Laparoscopic ultrasound may behelpful in the diagnosis and staging oflocal pancreatic lesions.[41] With thistechnique, the head and body of thepancreas are visualized by retroduodenalor infragastric approaches, respectively.When combined withlaparoscopic manipulations, laparoscopicultrasonography is able to assessthe size and extent of local disease.Improvements in RadiationTherapyIntraoperative Electron-BeamTherapy
Because of the high rates of localprogression following EBRT and5-FU-based chemotherapy, many investigatorshave evaluated the role ofintraoperative radiation therapy (IORT)in patients with locally advanced pancreaticcancer. The median survival ofpatients in these trials did not seem tobe superior to those studies without theuse of IORT. In a phase II study atThomas Jefferson University Hospital,local failure was reported in 31% ofpatients. In a Mayo Clinic retrospectivestudy of 159 patients treated similarlywith 5-FU and EBRT, with somepatients receiving an additional boostof IORT, local control was significantlyhigher at 1 year (82% vs 66%)and 2 years (48% vs 20%) in the patientsreceiving IORT. Nevertheless,survival was similar in both groups. Ithas become clear that the rapid appearanceof metastatic disease offsetsany improvement in local control offeredby intraoperative radiation therapy(Table 3).[42-44]Three-Dimensional ConformalRadiation Therapy
Three-dimensional conformal radiationtherapy is also being appliedto treatment of patients with pancreaticcancer. This CT-based treatmentis designed to allow "unconventional"beam orientations at the target site,permitting coverage with higher targetvolume and reduced irradiation tonontargeted tissues. For irradiation ofthe pancreas, it is important to reduceharmful doses to other organs such asthe kidney, especially given themarked radiosensitivity of this organ.This has been successfully performedwith 3D conformal radiotherapy byoptimizing beam orientation andweightings to reduce the dose receivedby other nearby organs. By an intensity-modulated approach, the techniquehas been further refined so thatinverse treatment planning can be performed.Here, a computer-based treatmentprotocol is devised, including anonuniform radiation treatment thatis delivered to the target, negating thestandard trial-and-error planning approachused in the past. As these techniquesevolve, it is likely thatever-increasing improvements in radiationdosing and treatment tolerancewill be observed with reduced surroundingtissue morbidities. Additional techniqueswill likely include positronemission tomography and CT fusion.Newer ChemotherapeuticsCombined With RadiationTherapyNew cytotoxic agents and targetedtherapies are being investigated in severalclinical trials. Many are being studiedin combination with gemcitabine,the standard first-line agent in patientswith advanced and metastatic cancerof the pancreas. Agents being evaluatedinclude chemotherapeutic agents (eg,irinotecan [CPT-11, Camptosar-a topoisomeraseI inhibitor], docetaxel[Taxotere], oxaliplatin [Eloxatin], pemetrexed[Alimta, an antifolate]); andmolecularly targeted agents (eg, tipifarnib[R-115777, a farnesyltransferaseinhibitor], trastuzumab [Herceptin, ananti-HER2/neu antibody], and cetuximab[Erbitux, an epidermal growthfactor receptor inhibitor], and smallmoleculeinhibitors of epidermal growthfactor receptor, such as gefitinib [Iressa]or erlotinib [Tarceva] and bevacizumab[Avastin]).A number of approaches utilizinggene therapy are in trials. ONYX-015,an E1B 55-kD gene-deleted replication-selective adenovirus, is beingstudied in a phase I trial in 21 patientswith locally advanced or metastaticdisease. The virus is injected by endoscopicultrasound into unresectablepancreatic carcinomas and deliveredover 8 weeks at doses of 2 *10¹⁰ to2 *10¹¹ particles/treatment, combinedwith gemcitabine (1,000 mg/m²) forthe last 3 weeks.[45] Early results haveindicated some activity: 2 of 21 patientshad partial tumor regression, 2experienced minor responses, 6 hadstable disease, and 11 experienced progressionor were removed from thestudy due to treatment toxicities.Phase II/III trials are ongoing.Immunologic approaches are alsounder evaluation, especially usingvaccines. Here, immunotherapy is perceivedas having the potential to offeralternative mechanisms of antitumoractivity in an integrated approach withcurrent regimens such as surgery orchemoradiation. For example, resultsof a phase I study using an interferonmodifiedwhole-cell irradiated tumorvaccine with granulocyte-macrophagecolony-stimulating factor (GM-CSF)showed that median survival withtreatment was 19 weeks in 15 evaluablepatients with metastatic disease;7 patients survived > 6 months and 4patients survived > 50 weeks.[46] Theanalysis also revealed a strong correlationfor survival with a decrease inthe marker CA 19-9 within 6 weeksof treatment, thus showing a biologicresponse to the vaccine that was notidentified by imaging studies. Ongoingstudies are underway.The effects of a novel GM-CSF-secreting pancreatic tumor vaccine forthe treatment of patients with surgicallyresected cancer of the pancreashas also been studied.[47] In this phaseI trial, 14 patients with stage I-IIIcancer were administered the vaccine8 weeks after pancreaticoduodenectomyat doses of 1-50 107 vaccinecells. Twelve of the patients then receivedchemoradiation for an additional6 months following surgery.Six patients completed chemoradiationtreatment and received three additionalmonthly vaccinations. Threeof the patients have remained diseasefreefor at least 25 months after diagnosis.Further evaluation of thevaccine is ongoing, as it was suggestedthat the vaccine may inducedose-dependent systemic antitumorimmune response.ConclusionThe treatment of pancreatic cancerremains a formidable challenge. Technologicaladvances in imaging andsurgery have allowed more precisestaging and administration of radiationto patients with locally advancedpancreatic cancer. Studies performedin the 1980s and 1990s have demonstratedthat palliation is achievable fora high percentage of patients, especiallyvia a combined-modality approach.For patients with goodperformance status, chemoradiation isthe treatment of choice. For those withmarginal or poor performance status,single-agent gemcitabine is a reasonablealternative to prolong survivaland improve quality of life. Despiteadvances in palliation, the limited increasein survival benefit achieved todate warrants additional clinical trialsto further improve adjuvant therapies,radiation treatment fields, and dose/fractionation combinations, and toexplore the potential of novel biologictherapies.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Pancreatic Cancer (PDQ): Treatment.National Cancer Institute. February 19, 2003.

2.

Jemal A, Murray T, Samuel S, et al: Cancerstatistics 2003. CA Cancer J Clin 53:5-26,2003.

3.

Yeo CJ, Abrams RA, Grochow LB, et al:Pancreaticoduodenectomy for pancreatic adenocarcinoma:Postoperative adjuvant chemotherapyimproves survival. A prospective,single-institution experience. Ann Surg 5:621-633, 1997.

4.

Cancer Facts and Figures 2003. Atlanta,American Cancer Society, 2003.

5.

Sohn TA, Lillemoe KD, Cameron JC,et al: Surgical palliation of unresectableperiampullary adenocarcinoma in the 1990s.J Am Coll Surg 188:658-666, 1999.

6.

Baron TH: Expandable metal stents forthe treatment of cancerous obstruction of thegastrointestinal tract. N Engl J Med 344:1681-1687, 2001.

7.

Conlon KC, Klimston DS, Brannan MF,et al: Long-term survival after curative resectionfor pancreatic ductal adenocarcinoma:Clinicopathologic analysis of 5-year survivors.Ann Surg 223:273-279, 1996.

8.

Evans DB, Abbruzzese JL, Willet CG:Cancer of the pancreas, in DeVita VT Jr,Hellman S, Rosenberg SA (eds): Cancer Principles& Practice of Oncology (6th ed), pp1126-1127. Philadelphia, Lippincott Williams& Wilkins, 2001.

9.

Anonymous: Further evidence of effectiveadjuvant combined radiation and chemotherapyfollowing curative resection of pancreaticcancer. Gastrointestinal Tumor StudyGroup. Cancer 59:2006-2010, 1987.

10.

Klinkenbijl JH, Jeekel J, Sahmoud T,et al: Adjuvant radiotherapy and 5-fluorouracilafter curative resection of cancer of the pancreas and periampullary region: Phase III trialof the EORTC Gastrointestinal Tract CancerGroup. Ann Surg 130:776-782, 1999.

11.

Neoptolemos JP, Dunn JA, Stocken DD,et al: Adjuvant chemoardiotherapy and chemotherapyin resectable pancreas cancer:A randomizedcontrolled trial. Lancet358:1576-1585, 2001.

12.

Breslin TM, Hess HR, Harbison DB,et al: Neoadjuvant chemoradiotherapy for adenocarcinomaof the pancreas: Treatment variablesand survival duration. Ann Surg Oncol8:123-132, 2001.

13.

Arnoletti JP, Hoffman JP, Ross EA,et al: Preoperative chemoradiation in the managementof adenocarcinoma of the body of thepancreas. Am Surg 68:330-335, 2002.

14.

Moertel CG, Childs DS Jr, Reitmeier RJ,et al: Combined 5-fluorouracil and supervoltageradiation therapy of locally unresectablegastrointestinal cancer. Lancet 2:865-867,1969.

15.

Moertel CG, Frytak S, Hahn RG, et al:Therapy of locally unresectable pancreatic carcinoma:A randomized comparison of high dose(6000 rads) radiation alone, moderate dose radiation(4000 rads + 5-fluorouracil) and highdose radiation + 5-fluorouracil. The GastrointestinalTumor Study Group. Cancer48:1705-1710, 1981.

16.

Anonymous: Radiation therapy combinedwith Adriamycin or 5-fluorouracil for thetreatment of locally resectable pancreatic carcinoma.Cancer 56:2563-2568, 1985.

17.

Anonymous: Treatment of locallyunresectable carcinoma of the pancreas: Comparisonof combined-modality therapy (chemotherapyplus radiotherapy) to chemotherapyalone. Gastrointestinal Tumor Study Group.J Natl Cancer Inst 80:751-755, 1988.

18.

Klaassen DJ, MacIntyre JM, Catton GE,et al. Treatment of locally unresectable cancerof the stomach and pancreas: A randomizedcomparison of 5-fluorouracil alone with radiationplus concurrent and maintenance 5-fluorouracilSMQ-8212-SMQAn Eastern Cooperative OncologyGroup study. J Clin Oncol 3:373-378, 1985.

19.

Burris HA 3rd, Moore MJ, Andersen J,et al: Improvements in survival and clinicalbenefit with gemcitabine as first-line therapyfor patients with advanced pancreas cancer: Arandomized trial. J Clin Oncol 15:2403-2413,1997.

20.

Berlin JD, Catalano P, Thomas JP, et al:Phase III study of gemcitabine in combinationwith fluorouracil versus gemcitabine alone inpatients with advanced pancreatic carcinoma:Eastern Cooperative Oncology Group TrialE2297. J Clin Oncol 20:3270-3275, 2002.

21.

Wein A, Wehler M, Fischer B, et al: PhaseII study with weekly 24-hour infusion (24-hinf.) of high-dose 5-fluorouracil (5-FU) andgemcitabine (GEM) in metastatic pancreas cancer(UICC IVb): Final results (abstract 620).Proc Am Soc Clin Oncol 21:156a, 2002.

22.

Blackstock AW, Tempero MA,Niedwiecki D, et al: Cancer and LeukemiaGroup B (CALGB) 89805: Phase IIchemoradiation trial using gemcitabine in patientswith locoregional adenocarcinoma of thepancreas (abstract 627). Proc Am Soc ClinOncol 20:158a, 2001.

23.

Safran H, Moore T, Iannitti D, et al:Paclitaxel and concurrent radiation for locallyadvanced pancreatic cancer. Int J Radiat OncolBiol Phys 49:1275-1279, 2001.

24.

Whittington R, Solin L, Mohiuddin M,et al: Multimodality therapy of localizedunresectable pancreatic adenocarcinoma. Cancer54:1991-1998, 1984.

25.

Jessup JM, Steele G, Mayer RJ, et al:Neoadjuvant therapy for unresectable pancreaticadenocarcinoma. Arch Surg 128:559-564,1993.

26.

Pipas JM, Mitchell SE, Barth RJ Jr,et al: Phase I study of twice-weeklygemcitabine and concomitant external-beamradiotherapy in patients with adenocarcinomaof the pancreas. Int J Radiat Oncol Biol Phys50:1317-1322, 2001.

27.

Epelbaum R, Rosenblatt E, Nasrallah S,et al: Phase II study of gemcitabine combinedwith radiation therapy in patients with localized,unresectable pancreatic cancer. J SurgOncol 81:138-143, 2002.

28.

Crane CH, Janjan N, Evans D, et al: Toxicityand efficacy of concurrent gemcitabineand radiotherapy for locally advanced pancreaticcancer. Int J Gastrointest Cancer 29:9-18,2001

29.

Termuhlen PM, Evans DB, Willett CG:IORT in pancreatic cancer, in Gunderson LL,Willett CG, Harrison LB, et al (eds): IntraoperativeIrradiation Techniques and Results, pp201-222. Totowa, NJ, Humana, 1999.

30.

Haslam JB, Cavanaugh PJ, Stroup SL:Radiation therapy in the treatment ofirresectable adenocarcinoma of the pancreas.Cancer 32:1341-1345, 1973.

31.

Dobelbower RR, Borgelt BB, StrublerKA, et al: Precision radiotherapy for cancer ofthe pancreas: Technique and results. Int JRadiat Oncol Biol Phys 6:1127-1133, 1980.

32.

Tamm E, Charnsangavej C, Szklaruk J:Advanced 3-D imaging for the evaluation ofpancreatic cancer with multidetector CT. Int JGastrointest Cancer 30:65-71, 2001.

33.

Warshaw AL, Gu ZY, Wittenberg J,et al: Preoperative staging and assessment ofresectability of pancreatic cancer. Arch Surg125:230-233, 1990.

34.

Wiersema MJ: Accuracy of endoscopicultrasound in diagnosing and staging pancreaticcarcinoma. Pancreatology 1:625-632,2001.

35.

Kahl S, Glassbrenner B, ZimmermannS, et al: Endoscopic ultrasound in pancreaticdisease. Dig Dis 20:120-126, 2002.

36.

Brugge WR, Van Dam J: Pancreatic andbiliary endoscopy. N Engl J Med 341:1808-1816, 1999.

37.

Ahmad NA, Shah JN, Kochman ML:Endoscopic ultrasonography and endoscopicretrograde cholangiopancreatography imagingfor pancreaticobiliary pathology: The gastroenterologistSMQ-8217-SMQsperspective. Radiol Clin NorthAm 40:1377-1395, 2002.

38.

Fernandez-del Castillo C, Rattner DW,Warshaw AL, et al: Further experience withlaparoscopy and peritoneal cytology in the stagingof pancreatic cancer. Br J Surg 82:1127-1129, 1995.

39.

Minniti S, Bruno C, Blasiutti C, et al:Sonography versus helical CT in identificationand staging of pancreatic ductal adenocarcinoma.J Clin Ultrasound 31:175-182, 2003.

40.

Van de Walle P, Blomme Y, Van OutryveL: Hand-assisted staging laparoscopy for sussuspectedmalignancies of the pancreas. Acta ChirBelg 102:183-186, 2002.

41.

Kwon AH, Inui H, Kamiyama Y: Preoperativelaparoscopic examination using surgicalmanipulation and ultrasonography for pancreaticlesions. Endoscopy 34:464-468, 2002.

42.

Shipley WU, Wood WC, Tepper JE,et al: Intraoperative electron beam irradiationfor patients with unresectable pancreatic carcinoma.Ann Surg 200:289-296, 1984.

43.

Tepper JE, Shipley WU, Warshaw AL,et al: The role of misonidazole combined withintraoperative radiation therapy in the treatmentof pancreatic carcinoma. J Clin Oncol 5:579-584, 1987.

44.

Garton GR, Gunderson LL, NagorneyDM, et al: High-dose preoperative externalbeam and intraoperative irradiation for locallyadvanced pancreatic cancer. Int J Radiat OncolBiol Phys 27:1153-1157, 1993.

45.

Hecht JR, Bedford R, Abbruzzese JL,et al: A phase I/II trial of intratumoral endoscopicultrasound injection of ONYX-015 withintravenous gemcitabine in unresectable pancreaticcarcinoma. Clin Cancer Res 9:555-561,2003.

46.

Wiseman CL, Kharazi A, Berliner K,et al: Whole-cell vaccine/GMSCF therapy inpancreas cancer patients: Strong correlation betweenlonger survival and decrease in serumCA 19-9 (abstract 1873). Proc Am Soc ClinOncol 21:16b, 2002.

47.

Jaffee EM, Hruban RH, Biedrzycki B,et al: Novel allogeneic granulocyte macrophagecolony-stimulating factor-secreting tumorvaccine for pancreatic cancer: A phase I trialof safety and immuno activation. J Clin Oncol19:145-156, 2001.