Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Evaluating the Impact of a Single-Day Multidisciplinary Clinic on the Management of Pancreatic Cancer A phase II study of oral S-1 with concurrent radiotherapy followed by chemotherapy with S-1 alone for locally advanced pancreatic cancer Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer Radiotherapy technical considerations in the management of locally advanced pancreatic cancer: American-French consensus recommendations. Phase II study of oral S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Phase I Trial of Consolidative Radiotherapy with Concurrent Bevacizumab, Erlotinib and Capecitabine for Unresectable Pancreatic Cancer Phase II Study of Radiation Therapy Combined With Weekly Low-Dose Gemcitabine for Locally Advanced, Unresectable Pancreatic Cancer Role of neoadjuvant concurrent chemoradiation in locally advanced unresectable pancreatic cancer: a feasibility study at tertiary care centre. Survival after combined modality therapy for pancreatic cancer. GEMOX plus tomotherapy for unresectable locally advanced pancreatic cancer. Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Induction gemcitabine plus concurrent gemcitabine and radiotherapy for locally advanced unresectable or resected pancreatic cancer. Phase II trial of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer Toxicity study of gemcitabine, oxaliplatin, and bevacizumab, followed by 5-fluorouracil, oxaliplatin, bevacizumab, and radiotherapy, in patients with locally advanced pancreatic cancer Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. Phase 1 pharmacogenetic and pharmacodynamic study of sorafenib with concurrent radiation therapy and gemcitabine in locally advanced unresectable pancreatic cancer. Phase 2 Multi-institutional Trial Evaluating Gemcitabine and Stereotactic Body Radiotherapy for Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma A phase II trial of two durations of Bevacizumab added to neoadjuvant gemcitabine for borderline and locally advanced pancreatic cancer. Phase 2 trial of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer. Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer. Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma. Phase I/II Trial of Induction Chemotherapy Followed by Concurrent Chemoradiotherapy and Surgery for Locoregionally Advanced Pancreatic Cancer Phase II study of bevacizumab with concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic cancer: Radiation Therapy Oncology Group RTOG 0411. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. A randomized phase II study of gemcitabine plus S-1 versus gemcitabine alone in patients with unresectable pancreatic cancer. Local staging of pancreatic cancer: criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical CT. A multicenter phase II study of gemcitabine and S-1 combination chemotherapy in patients with unresectable pancreatic cancer Phase II Trial of Induction Gemcitabine/CPT-11 Followed by a Twice-Weekly Infusion of Gemcitabine and Concurrent External Beam Radiation for the Treatment of Locally Advanced Pancreatic Cancer Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205.
PURPOSE To provide evidence -based recommendations to oncologists and others for treatment of patients with locally advanced , unresectable pancreatic cancer . METHODS American Society of Clinical Oncology convened an Expert Panel of medical oncology , radiation oncology , surgical oncology , gastroenterology , palliative care , and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015 . Outcomes included overall survival , disease-free survival , progression-free survival , and adverse events . RESULTS Twenty-six r and omized controlled trials met the systematic review criteria . RECOMMENDATIONS A multiphase computed tomography scan of the chest , abdomen , and pelvis should be performed . Baseline performance status and comorbidity profile should be evaluated . The goals of care , patient preferences , psychological status , support systems , and symptoms should guide decisions for treatments . A palliative care referral should occur at first visit . Initial systemic chemotherapy ( 6 months ) with a combination regimen is recommended for most patients ( for some patients radiation therapy may be offered up front ) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile . There is no clear evidence to support one regimen over another . The gemcitabine-based combinations and treatments recommended in the metastatic setting ( eg , fluorouracil , leucovorin , irinotecan , and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel ) have not been evaluated in r and omized controlled trials involving locally advanced , unresectable pancreatic cancer . If there is local disease progression after induction chemotherapy , without metastasis , then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile . If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities , radiation therapy may be offered as an alternative . Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline . Follow-up visits every 3 to 4 months are recommended . Additional information is available at www.asco.org/ guidelines /LAPC and www.asco.org/ guidelines /MetPC and www.asco.org/ guidelines wiki Purpose To evaluate the impact of a multidisciplinary clinic on the clinical care recommendations of patients with pancreatic cancer compared with the recommendations the patients received prior to review by the multidisciplinary tumor board . Methods The records of 203 consecutive patients referred to the Johns Hopkins pancreatic multidisciplinary clinic were prospect ively collected from November 2006 to October 2007 .  Cross-sectional imaging , pathology , and medical history were evaluated by a panel of medical/radiation oncologists , surgical oncologists , pathologists , diagnostic radiologists , and geneticists . Alterations in treatment recommendations between the outside institution and the multidisciplinary clinic were recorded and compared . Results On presentation , the outside computed tomography ( CT ) report described locally advanced/unresectable disease ( 34.9 % ) , metastatic disease ( 17.7 % ) , and locally advanced disease with metastasis ( 1.1 % ) . On review of su bmi tted imaging and imaging performed at Hopkins , 38 out of 203 ( 18.7 % ) patients had a change in the status of their clinical stage . Review of the histological slides by dedicated pancreatic pathologists result ed in changes in the interpretation for 7 of 203 patients ( 3.4 % ) . Overall , 48 out of 203 ( 23.6 % ) patients had a change in their recommended management based on clinical review of their case by the multidisciplinary tumor board . Enrollment into the National Familial Pancreas Tumor Registry increased from 52 out of 106 ( 49.2 % ) patients in 2005 to 158 out of 203 ( 77.8 % ) with initiation of the multidisciplinary clinic . Conclusion The single-day pancreatic multidisciplinary clinic provided a comprehensive and coordinated evaluation of patients that led to changes in therapeutic recommendations in close to one-quarter of patients Background / purpose S-1 is a new oral fluoropyrimidine anticancer agent shown to be effective for pancreatic cancer . In a previous phase I trial , we evaluated the safety of S-1 combined with radiotherapy to determine the maximum tolerated dose and dose-limiting toxicity in patients with unresectable pancreatic cancer . The recommended dose of S-1 for phase II trials of chemoradiotherapy was determined as 80 mg/m2/day given on days 1–21 of a 28-day cycle . This phase II study was conducted to further evaluate the efficacy and toxicity of radiotherapy combined with S-1 ( UMIN000004794 ) . Methods Eligible patients had locally advanced and unresectable pancreatic cancer without distant metastases , an Eastern Cooperative Oncology Group performance status of 0–1 , adequate organ and marrow functions , and no prior anticancer therapy . Patients initially received 4 weeks of chemoradiotherapy . S-1 was given orally at a dose of 80 mg/m2/day twice daily on days 1–21 . Radiotherapy was delivered in fractions of 1.25 Gy twice daily , 5 days per week for 4 weeks ( total dose : 50 Gy in 40 fractions ) . One month after the completion of chemoradiotherapy , S-1 was administered for 14 days followed by a 14-day rest period . This cycle was repeated as maintenance therapy until disease progression or unacceptable toxicity . Results Fifty patients were enrolled in this phase II study . Median follow-up was 14.6 months ( range 5.4–58.9 months ) . Forty-three patients ( 86 % ) completed the scheduled course of chemoradiotherapy . There was no treatment-related death or grade 4 toxicity . The major toxic effects were leukopenia and nausea . The objective tumor response according to the Response Evaluation Criteria in Solid Tumours criteria was partial response in 15 patients ( 30 % ) ( 95 % confidence interval ( CI ) , 18–45 % ) , stable disease in 23 ( 46 % ) , and progressive disease in 12 ( 24 % ) . Median progression-free survival and median overall survival were 6.7 months ( 95 % CI , 4.7–11.2 months ) and 14.3 months ( 95 % CI , 10.8–20.8 months ) , respectively . Survival rates at 1 and 2 years were 62 and 27 % , respectively . Conclusions Combination therapy with S-1 and radiation in patients with locally advanced and unresectable pancreatic cancer is considered a promising , well-tolerated regimen that can be recommended as an effective treatment for locally advanced pancreatic cancer Purpose For unresectable locally advanced ( UR-LA ) pancreatic cancer , chemoradiotherapy has been recommended by the NCCN guidelines . We design ed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine ( GnP ) for patients with UR-LA pancreatic cancer . The purpose of this phase I study was to determine a recommended dose ( RD ) for this novel regimen . Methods Patients with UR-LA pancreatic cancer were eligible . The frequency of dose-limiting toxicities ( DLTs ) was evaluated , and the RD was determined . Patients were classified according to the design ated dose levels of chemoradiotherapy using the GnP regimen . After additional 6 cycles of the GnP regimen were administered , surgery was considered if the patients had stable disease and tumor marker levels had normalized . Results DLT ( grade 4 thrombocytopenia ) was observed only in 1 of 12 patients , and the RD was set at level 3 . Grade 3–4 leukopenia was observed in 9 ( 75.0 % ) patients , and neutropenia in 7 ( 58.3 % ) . The response rate was 41.7 % , and the disease control rate was 100 % . Conversion surgery was performed in 6 ( 50 % ) patients , and curative resection ( R0 ) was performed in all 6 patients ( 100 % ) . Stratification according to the Evans classification system demonstrated one patient with grade 1b , one with grade 2 , two with grade 3 , and two with grade 4 disease . Conclusion The RD for weekly administration was 800 mg/m2 for gemcitabine and 100 mg/m2 for nab-paclitaxel with a 50.4 Gy radiation . The GnP regimen at this dosage was promising with 6 of 12 patients proceeding to conversion surgery , and should be evaluated further in a phase II trial Pancreatic carcinoma is a leading cause of cancer-related mortality . Approximately 30 % of pancreatic cancer patients present with locally advanced , unresectable nonmetastatic disease . For these patients , two therapeutic options exist : systemic chemotherapy or chemoradiotherapy . Within this context , the optimal technique for pancreatic irradiation is not clearly defined . A search to identify relevant studies was undertaken using the Medline data base . All Phase III r and omized trials evaluating the modalities of radiotherapy in locally advanced pancreatic cancer were included , as were some noncontrolled Phase II and retrospective studies . An expert panel convened with members of the Radiation Therapy Oncology Group and GERCOR cooperative groups to review identified studies and prepare the guidelines . Each member of the working group independently evaluated five endpoints : total dose , target volume definition , radiotherapy planning technique , dose constraints to organs at risk , and quality assurance . Based on this analysis of the literature , we recommend either three-dimensional conformal radiation therapy or intensity-modulated radiation therapy to a total dose of 50 to 54 Gy at 1.8 to 2 Gy per fraction . We propose gross tumor volume identification to be followed by an expansion of 1.5 to 2 cm anteriorly , posteriorly , and laterally , and 2 to 3 cm craniocaudally to generate the planning target volume . The craniocaudal margins can be reduced with the use of respiratory gating . Organs at risk are liver , kidneys , spinal cord , stomach , and small bowel .  Stereotactic body radiation therapy should not be used for pancreatic cancer outside of clinical trials . Radiotherapy quality assurance is m and atory in clinical trials . These consensus recommendations are proposed for use in the development of future trials testing new chemotherapy combinations with radiotherapy . Not all of these recommendations will be appropriate for trials testing radiotherapy dose or dose intensity concepts PURPOSE S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer . The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer . METHODS AND MATERIAL S Patients with histopathologically proven , unresectable , locally advanced pancreatic cancer were eligible .  Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks . S-1 was administered orally twice a day at a dose of 80 mg/m(2)/day from day 1 to 14 and 22 to 35 . Two weeks after the completion of chemoradiotherapy , maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression . RESULTS Thirty-four patients were enrolled in this study . The most common Grade 3 toxicities during chemoradiotherapy were anorexia ( 24 % ) and nausea ( 12 % ) . The overall response rate was 41 % ( 95 % confidence interval , 25%-58 % ) and overall disease control rate ( partial response plus stable disease ) was 97 % . More than 50 % decrease in serum CA 19 - 9 was seen in 27 of 29 evaluable patients ( 93 % ) . The median progression-free survival was 8.7 months . The median overall survival and 1-year survival rate were 16.8 months and 70.6 % , respectively . CONCLUSIONS Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer . This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion Purpose To determine the safety , tolerability and maximum tolerated dose ( MTD ) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation ( CRT ) in unresectable pancreatic cancer . Methods Seventeen patients with CT-staged , biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010 . Prior chemotherapy was permitted . Two patients each were enrolled at dose levels ( DLs ) 1–4 and 9 patients at DL 5 . All patients received 50.4 Gy ( GTV only ) in 28 fractions with concurrent capecitabine , bevacizumab and erlotinib . Dose of each drug was escalated in 5 DLs using the continual re assessment method . Bevacizumab was escalated from 5mg/Kg q2weeks ( DLs 1–4 ) to 10mg/Kg q2weeks ( DL 5 ) ; daily erlotinib from 100mg/day ( DLs 1–2 ) to 150 mg/Kg ( DLs 3–5 ) ; and capecitabine from 400mg/m2 twice daily on days of radiation ( DL 1 ) to 650mg/m2 ( DLs 2–3 ) to 825 mg/m2 ( DLs 4–5 ) . Re assessment for potential resection was performed 6–8 weeks later . Results Sixteen patients received gemcitabine-based chemotherapy prior to CRT . With a median clinical follow-up of 10 months , no grade 3 toxicities were observed in DLs 1–4 . Three ( 33 % ) patients at DL 5 developed a grade 3 acute toxicity ( 2 diarrhea , 1 rash ) . No grade 4 or 5 toxicities were seen . DL 4 was selected as the MTD ; therefore , the recommended doses in combination with radiation are : bevacizumab , 5mg/Kg q2weeks ; erlotinib , 150 mg/Kg daily ; and capecitabine , 825mg/m2 BID . Median survival was 17.4 months . Of the five patients who underwent resection , 4 were originally deemed locally advanced and 1 was borderline resectable . Three patients had excellent pathological response ( 2 complete response and 20 % viable tumor ) at surgery , and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures . Conclusions This chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation Background : Through a phase I study with a fixed radiation dose of 54 Gy and escalating doses of weekly gemcitabine , we established a recommended dose of gemcitabine at 250 mg/m2 in combination with radiation therapy for patients with unresectable pancreatic cancer . Objective : The purpose of this phase-II study was to evaluate the safety and efficacy of the regimen which was established in the phase I study . Methods : In all patients with unresectable stage III and limited stage IV pancreatic cancer with no distant metastasis except for para-aortic lymph node involvement at a level as low as the left renal vein , a total dose of 54 Gy  was delivered in 30 fractions of 1.8 Gy/d . Gemcitabine was given weekly at a dose of 250 mg/m2 . Results : Between December 2002 and March 2006 , 22 patients were enrolled in this study and one withdrew after enrollment . Twenty of 21 patients ( 95 % ) completed the protocol therapy . Radiologic partial response was observed in 6 and stable disease was noted in 15 . Normalization of the tumor marker ( CA19 - 9 ) occurred in 61 % of patients . The 1-year survival rate was 74 % and the median survival time was 16.6 months . The major toxicity was leucopenia ; grade 3 in 14 ( 67 % ) , anorexia grade 3 in 2 ( 9.5 % ) , and grade 3 gastric ulcer in 2 ( 10 % ) in National Cancer Institute 's Common Terminology Criteria for Adverse Events version 3.0 ( NCI-CTCAE v3.0 ) . Neither grade 4 nor 5 was recognized . Conclusion : Treatment with gemcitabine combined with radiation therapy according to the present schedule is well tolerated and can provide prolonged survival in patients with localized , unresectable pancreatic cancer BACKGROUND Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance . There is a strong rationale for a neoadjuvant approach , since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease . The objective of the present study was to assess the effect of neoadjuvant chemoradiation therapy ( NACRT ) on tumor response , down staging and resection , toxicity and any survival advantage . MATERIAL S AND METHODS A prospect i ve pilot study was carried out from January 2009 to June 2011 in which 15 patients of locally advanced unresectable pancreatic cancer were included . All patients were treated with NACRT protocol with oral Capecitabine and 3D conformal radiotherapy ( 3DCRT ) of 30 Gy in 10 fractions . The patients were restaged 3 to 4 weeks after the completion of NACRT and explored for resection . RESULTS Out of 15 patients , fourteen were evaluable . Four patients underwent surgery , 5 had partial response but remained unresectable , 2 patients had stable disease and 3 had progressive disease . Most of the toxicities were slight and were in grade 1 to 2 . None of the patients developed grade 3 or 4 gastrointestinal or hematological toxicity . The median survival was 15 months for resected patients and 8.6 months for unresected patients , respectively . The 2 year actuarial overall survival was 34.6 % . CONCLUSION All patients with locally unresectable pancreatic cancer should be offered chemoradiation therapy , in hopes of down staging the tumor for possible resection and achieving higher survival Twenty consecutive patients with unresectable , locally advanced pancreatic cancer were treated with split courses of radiotherapy ( RT ) and simultaneous multidrug chemotherapy consisting of 5 fluorouracil , continuous infusion , streptozotocin , and cisplatin . A separate , retrospective study identified a group of 28 contemporary patients with less advanced pancreatic cancers , all of which were successfully resected . The survival rate of the two groups were similar over the first 2 years , although it initially favored the unresectable group . This pattern of survival among patients treated with combined modality therapy provides a basis for new studies . At the two clinical extremes , these include treatment of unresectable tumors previously considered ineligible for this treatment and initial treatment before resection of stage I tumors BACKGROUND / AIMS The aim of this prospect i ve phase II study was to evaluate the effect of neoadjuvant GEMOX plus helical tomotherapy on the resectability of locally advanced pancreatic cancer . METHODOLOGY Between November 2004 and July 2008 , 33 enrolled patients received gemcitabine ( GEM ) 1000 mg/m2 on day 1 , and oxaliplatin ( OX ) 100 mg/m2 on day 2 , every two weeks for 3 - 4 cycles . This was followed by radiotherapy ( 25 Gy , 5 fractions ) , 15 days after completion of GEMOX . Patients then received a further 3 - 4 cycles of GEMOX , underwent restaging and were evaluated for surgery . Potentially resectable patients were su bmi tted to surgery , while unresectable responders received further GEMOX and radiotherapy . RESULTS Toxicity to GEMOX was similar to that reported elsewhere and radiotherapy was also well tolerated . After treatment , one patient achieved a complete response , 14 had a partial response , 11 showed a stable disease , 6 progressed , and one was not evaluable . Eight patients ( 24 % ) underwent surgical laparotomy ( 7 radical pancreatic resections and one explorative laparotomy ) . CONCLUSIONS Our study shows the feasibility and potential efficacy of the GEMOX plus helical tomotherapy regimen in unresectable locally advanced pancreatic cancer Recent studies suggest that neoadjuvant chemoradiation can downstage locally advanced pancreatic tumors . There is limited evaluable data to support this approach . We review our experience with preoperative chemoradiation for surgically staged , locally advanced pancreatic cancer to determine whether patients are downstaged with multimodal therapy allowing for curative resection . A prospect ively collected data base from Memorial Sloan-Kettering Cancer Center was review ed . Patients admitted between January 1993 and March 1999 with locally advanced pancreatic adenocarcinoma were identified ( N = 163 ) .  Chemoradiation was administered to 87 ( 53.3 % ) of 163 , and regimens varied from st and ard 5-fluorouracil/gemcitabine-based therapies to experimental protocol s. Only three patients ( 3/87 ; 3.4 % ) had a sufficient clinical response on restaging to warrant reexploration . Of these , two thirds were unresectable on subsequent laparoscopy because of extensive vascular involvement or metastatic disease . Only one patient underwent a potentially curative resection , with a survival of 18 months despite negative margins and no nodal involvement . The overall median survival for all patients with locally advanced disease treated with  chemoradiation  was 11 months ( 6.5 months without multimodal therapy ; P = 0.004 ) . Although hemora-diation is associated with improved overall survival in locally advanced disease , it rarely leads to surgical “ downstaging ” allowing for potentially curative pancreatic resections . Novel multimodality approaches are required PURPOSE Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996 . Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 ( HER1/EGFR ) and this is associated with a worse prognosis . We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable , locally advanced , or metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned 1:1 to receive st and ard gemcitabine plus erlotinib ( 100 or 150 mg/d orally ) or gemcitabine plus placebo in a double-blind , international phase III trial . The primary end point was overall survival . RESULTS A total of 569 patients were r and omly assigned .  Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio ( HR ) of 0.82 ( 95 % CI , 0.69 to 0.99 ; P = .038 , adjusted for stratification factors ; median 6.24 months v 5.91 months ) . One-year survival was also greater with erlotinib plus gemcitabine ( 23 % v 17 % ; P = .023 ) . Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 ( 95 % CI , 0.64 to 0.92 ; P = .004 ) . Objective response rates were not significantly different between the arms , although more patients on erlotinib had disease stabilization . There was a higher incidence of some adverse events with erlotinib plus gemcitabine , but most were grade 1 or 2 . CONCLUSION To our knowledge , this r and omized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine . The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d PURPOSE The purpose of this study was to evaluate whether external-beam radiotherapy ( EBRT ) with concurrent continuous 5-fluorouracil ( 5-FU ) infusion affects the length and quality of survival in patients with locally unresectable pancreatic cancer . METHODS Thirty-one patients with histologically proven locally advanced and unresectable pancreatic cancer without distant metastases were evaluated in this prospect i ve r and omized trial . Sixteen patients received EBRT ( 50.4 Gy/28 fractions ) with concurrent continuous infusion of 5-FU ( 200 mg/m(2)/day ) , whereas 15 patients received no chemoradiation . The length and quality of survival was analyzed and compared for the two groups . RESULTS The median survival of 13.2 months and the 1-year survival rate of 53.3 % in the chemoradiation group were significantly better than the respective 6.4 months and 0 % in the group without chemoradiotherapy ( p = 0.0009 ) . The average monthly Karnofsky score , a quality of life indicator , was 77.1 in the chemoradiation group , which was significantly higher than the 65.5 in the group without chemoradiotherapy ( p < 0.0001 ) . The number of hospital days per month of survival was significantly less in the chemoradiation than in the no-therapy group ( 12.3 vs. 19.0 days , p < 0.05 ) . In the chemoradiation group , 5 patients ( 31 % ) had a partial response , and 9 ( 56 % ) had radiologically stable disease at a median duration of 6.1 months . The patients who had chemoradiation had a lower rate of liver and peritoneal metastases than patients without chemoradiotherapy ( 31 % vs. 64 % ) . Of 10 patients who experienced pain before chemoradiation , 8 ( 80 % ) received pain relief that lasted a median of 5.2 months . CONCLUSIONS EBRT with concurrent continuous 5-FU infusion increased the length and quality of survival as compared to no chemoradiotherapy and provided a definite palliative benefit for patients with unresectable pancreatic cancer PURPOSE Full-dose gemcitabine and concurrent radiotherapy is a promising treatment approach in unresectable pancreatic cancer . This study was conducted to assess the pattern of failure and toxicity associated with the use of conformal treatment volumes , omitting prophylactic lymph node irradiation . METHODS AND MATERIAL S Seventy-four patients with locally advanced pancreatic cancer were treated between 1997 and 2005 with full-dose ( 1000  mg/m(2 ) , Days 1 , 8 , and 15 ) gemcitabine and concurrent radiotherapy  ( 36 Gy [ median ] in 15 daily fractions ) . The planning target volume ( PTV ) was limited to the gross tumor volume ( GTV ) plus 1-cm margin . Patient computed tomography ( CT ) scans were systematic ally review ed to determine the pattern of failure . Kaplan-Meier and Cox-regression models were used to analyze freedom from local progression ( FFLP ) , distant failure , overall survival ( OS ) , and toxicity . RESULTS With a median follow-up of 10.6 months ( 20.6 months in living patients ) , the 1-year and 2-year FFLP rates were 64 % and 38 % , respectively . Four patients ( 5 % ) failed in the peripancreatic lymph nodes ( 3 in-field and 1 marginal failure ) . Median OS was 11.2 months . Analyzed as a time-dependent covariate , local failure was a significant predictor of OS ( p = 0.0074 ) . Sixteen patients ( 22 % ) had significant gastrointestinal ( GI ) toxicity ( > or = Grade 3 ) . PTV correlated with significant GI toxicity ( p = 0.007 ) . CONCLUSIONS Freedom from local progression in unresectable pancreatic cancer is suboptimal . In conjunction with full-dose gemcitabine , the use of conformal fields encompassing only the GTV helps reduce toxicity and does not result in marginal failures . Our findings provide rationale for intensification of local therapy in conjunction with more effective systemic therapy AIMS To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer . MATERIAL S AND METHODS Between March 2001 and August 2009 , 90 patients with unresectable ( 78 ) or resected ( 12 ) pancreatic cancer were treated with a st and ard treatment policy of induction gemcitabine ( seven doses of weekly gemcitabine at 1000 mg/m(2 ) ) followed by concurrent radiotherapy ( 52.5 Gy ) and biweekly gemcitabine ( 40 mg/m(2 ) ) . RESULTS After induction gemcitabine , 17.8 % of patients did not proceed to chemoradiotherapy , due to either disease progression , performance status deterioration or gemcitabine toxicity . Of the patients who received chemoradiotherapy , 68.9 % completed the course of 52.5 Gy , whereas 79.7 % received more than 45 Gy . Chemoradiotherapy was stopped early due to treatment toxicity in 22.9 % of patients . On intention to treat analysis , the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group . On multivariate analysis for the unresectable patients , a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival . CONCLUSION This large series confirms , in a st and ard practice setting , similar efficacy and tolerability of treatment as previously reported in our phase I-II study . The benefit to patients with a gross tumour volume > 48 cm(3 ) may be limited Purpose S-1 has a favorable effect in unresectable pancreatic cancer and a potential radiosensitizer . In addition , daily oral administration of S-1 is more convenient than continuous infusion of 5-fluorouracil . This study was design ed to evaluate the efficacy and safety of S-1 and concurrent radiotherapy in patients with locally advanced pancreatic cancer . Methods Eligibility criteria were histologically proven pancreatic adenocarcinoma , locally advanced disease , and no previous treatment .  S-1 was administered orally at a dose of 40 mg/m2 twice daily from day 1 to 14 and from day 22 to 35 , and concurrent radiotherapy ( a total dose of 50.4 Gy ) was delivered in 28 fractions . One month after treatment completion , tumor response was evaluated by computed tomography ( CT ) . Results A total of 25 patients were evaluable for efficacy and toxicity on the basis of the intention-to-treat analysis . The response rate and disease control rate were 24.0 and 68.0 % , respectively . There was no treatment-related death or grade 4 toxicity . The most common grade 3 hematologic and non-hematologic toxicities were thrombocytopenia ( 4.0 % ) and anorexia ( 20 % ) , respectively . All toxicities were tolerable and transient . The median time-to-progression and median overall survival were 6.5 months ( 95 % confidence interval , 4.1–9.0 months ) and 12.9 months ( 95 % confidence interval , 6.7–19.0 months ) , respectively , and the 1-year survival rate was estimated to be 43 % . Conclusions S-1 and concurrent radiotherapy shows favorable efficacy for disease control against locally advanced pancreatic cancer and was well tolerated with no severe toxicities Purpose Platinum compounds or bevacizumab , in combination with gemcitabine , achieved good response rates in early studies in advanced pancreatic cancer . This prompted an evaluation of an aggressive approach to allow better local control and resectability in locally advanced disease . Methods We piloted a combination of gemcitabine/oxaliplatin/bevacizumab Q2w for four cycles , followed by oxaliplatin and bevacizumab added to infusional 5-FU and radiotherapy , in patients with locally advanced pancreatic cancer . Results Nineteen patients were treated , of whom 17 completed the protocol -specified treatment . Median age was 60 years . Fifteen had unresectable , and four had borderline resectable disease .  Toxicity of chemotherapy was moderate : grade III neutropenia ( 5 ) and grade I/II nausea , vomiting , fatigue , and neuropathy . During chemoradiation , major grade III toxicities were nausea and vomiting ( 3 each ) . One patient had intractable pain early on , necessitating treatment cessation . Response rate for 18 evaluable patients was 11 % ( by RECIST ) ; five patients ( 4 inoperable , 1 borderline , 26 % ) went on to have surgery . One-year overall survival was 58 % and progression-free survival was 37 % . Conclusions This combination , associated with higher response rates in metastatic disease , had a lower than expected response rate in primary tumors . Although tolerable , our approach failed to affect clinical outcomes meaningfully PURPOSE The purpose of this trial was to evaluate the role of radiation therapy with concurrent gemcitabine ( GEM ) compared with GEM alone in patients with localized unresectable pancreatic cancer . PATIENTS AND METHODS Patients with localized unresectable adenocarcinoma of the pancreas were r and omly assigned to receive GEM alone ( at 1,000 mg/m(2)/wk for weeks 1 to 6 , followed by 1 week rest , then for 3 of 4 weeks ) or GEM ( 600 mg/m(2)/wk for weeks 1 to 5 , then 4 weeks later 1,000 mg/m(2 ) for 3 of 4 weeks ) plus radiotherapy ( starting on day 1 , 1.8 Gy/Fx for total of 50.4 Gy ) . Measurement of quality of life using the Functional Assessment of Cancer Therapy-Hepatobiliary question naire was also performed . RESULTS Of 74 patients entered on trial and r and omly assigned to receive GEM alone ( arm A ; n = 37 ) or GEM plus radiation ( arm B ; n = 34 ) , patients in arm B had greater incidence of grade s 4 and 5 toxicities ( 41 % v 9 % ) , but grade s 3 and 4 toxicities combined were similar ( 77 % in A v 79 % in B ) . No statistical differences were seen in quality of life measurements at 6 , 15 to 16 , and 36 weeks . The primary end point was survival , which was 9.2 months ( 95 % CI , 7.9 to 11.4 months ) and 11.1 months ( 95 % CI , 7.6 to 15.5 months ) for arms A and B , respectively ( one-sided P = .017 by stratified log-rank test ) . CONCLUSION This trial demonstrates improved overall survival with the addition of radiation therapy to GEM in patients with localized unresectable pancreatic cancer , with acceptable toxicity PURPOSE To define the safety , efficacy , and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy ( CRT ) in locally advanced pancreatic cancer . METHODS AND MATERIAL S Patients received gemcitabine 1000 mg/m(2 ) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT . Weekly gemcitabine 600 mg/m(2 ) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions . Sorafenib was dosed orally 400 mg twice daily until progression , except during CRT when it was escalated from 200 mg to 400 mg daily , and 400 mg twice daily . The maximum tolerated dose cohort was exp and ed to 15 patients . Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms ( VEGF-A and VEGF-R2 single nucleotide polymorphisms ) . RESULTS Twenty-seven patients were enrolled . No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT . The most common grade 3/4 toxicities were fatigue , hematologic , and gastrointestinal . The maximum tolerated dose was sorafenib 400 mg twice daily . The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months , respectively . The median overall survival for patients with VEGF-A -2578 AA , -1498 CC , and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months . Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans ) in responding patients . CONCLUSIONS Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer . Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival This phase 2 multi‐institutional study was design ed to determine whether gemcitabine ( GEM ) with fractionated stereotactic body radiotherapy ( SBRT ) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single‐fraction SBRT in patients with locally advanced pancreatic cancer ( LAPC ) PURPOSE The prognosis for unresectable pancreatic cancer remains dismal ( 1-year survival rate , < 10 % ; 5-year survival rate , < 5 % ) . Recent advances in conventional chemotherapy and novel molecular treatment strategies warrant investigation . This , the largest r and omized study in pancreatic cancer performed to date , compares marimastat , the first of a new class of agents , with gemcitabine . PATIENTS AND METHODS Four hundred fourteen patients with unresectable pancreatic cancer were r and omized to receive marimastat 5 , 10 , or 25 mg bid or gemcitabine 1,000 mg/m2 . The primary end point was survival . Progression-free survival , patient benefit , and safety were also assessed . RESULTS There was no significant difference in survival between 5 , 10 , or 25 mg of marimastat and gemcitabine ( P = .19 ) . Median survival times were 111 , 105 , 125 , and 167 days , respectively , and 1-year survival rates were 14 % , 14 % , 20 % , and 19 % , respectively . There was a significant difference in survival rates between patients treated with gemcitabine and marimastat 5 and 10 mg ( P < .003 ) . Both agents were well tolerated , although grade 3 or 4 toxicities were reported in 22 % and 12 % of the gemcitabine- and marimastat-treated patients , respectively . The major toxicity of marimastat was musculoskeletal ( 44 % of marimastat patients , compared with 12 % of gemcitabine patients ; musculoskeletal toxicity was severe in only 8 % of marimastat patients ) . CONCLUSION The results of this study provide evidence of a dose response for marimastat in patients with advanced pancreatic cancer . The 1-year survival rate for patients receiving marimastat 25 mg was similar to that of patients receiving gemcitabine . In view of the manageable tolerability of marimastat and its ease of administration , further studies are warranted Gemcitabine has been reported to be a potent radiosensitiser in human pancreatic cell lines . This study was conducted to evaluate the efficacy and toxicity of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer . In all , 42 patients with pancreatic cancer that was unresectable but confined to the pancreatic region were treated with external-beam radiation ( 50.4 Gy in 28 fractions over 5.5 weeks ) and weekly gemcitabine ( 250 mg m−2 , 30-min infusion ) . Maintenance gemcitabine ( 1000 mg m−2 weekly × 3 every 4 weeks ) was initiated 1 month after the completion of the chemoradiotherapy and continued until disease progression or unacceptable toxicity . Of the 42 patients , 38 ( 90 % ) completed the scheduled course of chemoradiotherapy . The major toxicity was leucopenia and anorexia . There was one death attributed to duodenal bleeding and sepsis . The median survival time was 9.5 months and the 1-year survival rate was 28 % . The median progression-free survival time was 4.4 months . In 35 patients with documented disease progression at the time of analysis , 34 ( 97 % ) showed distant metastasis as the cause of the initial disease progression . The chemoradiotherapy used in this study has a moderate activity against locally advanced pancreatic cancer and an acceptable toxicity profile . Future investigations for treatment with more systemic effects are warranted This prospect i ve study was undertaken to assess toxicity , resectability , and survival in pancreatic adenocarcinoma patients presenting with locally advanced , unresectable disease treated with neoadjuvant gemcitabine , docetaxel , and capecitabine ( GTX ) and gemcitabine and capecitabine (GX)/radiation therapy ( RT ) BACKGROUND We report the results of a phase II trial of adding the anti-ascular endothelial growth factor ( VEGF ) bevacizumab to gemcitabine neoadjuvant chemotherapy for patients with borderline and unresectable non-metastatic pancreatic cancer . PATIENTS AND METHODS Patients were assigned to one of the two treatment arms . Both groups received 1,000 mg/m(2 ) gemcitabine on days 1 , 8 , and 15 of a 4-week cycle for a total of four cycles . Group 1 received 5 mg/kg bevacizumab for six weeks ( three doses ) , every second week , starting at week 6 of gemcitabine therapy . Group 2 received 5 mg/kg bevacizumab for 12 weeks ( six doses ) , every second week , starting at week 1 of gemcitabine therapy . The objective of the present study was to assess the rate of complete radical resection and overall survival . RESULTS A total of 30 patients were enrolled : 19 patients had unresectable and 11 patients had borderline-resectable pancreatic cancer . Eleven patients ( 37 % ) underwent resection . The median overall survival of patients who underwent tumor resection was 13 months ( 95 % confidence interval=11 - 15 months ) . CONCLUSION In general , adding bevacizumab to neoadjuvant gemcitabine does not improve outcomes for patients with locally advanced pancreatic cancer . However , in individual cases , surgery is consequently possible and prolonged survival may be observed PURPOSE To evaluate , in a phase 2 study , the safety and efficacy of induction gemcitabine , oxaliplatin , and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer ( BRPC or LAPC , respectively ) . METHODS AND MATERIAL S Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles , combined with weekly cetuximab . Patients were then restaged ; " downstaged " patients with resectable disease underwent attempted resection . Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy ( 54 Gy ) and concurrent capecitabine ;  patients with borderline resectable disease or better at restaging underwent attempted resection . RESULTS A total of 39 patients were enrolled , of whom 37 were evaluable . Protocol treatment was generally well tolerated . Median follow-up for all patients was 11.9 months . Overall , 29.7 % of patients underwent R0 surgical resection ( 69.2 % of patients with BRPC ; 8.3 % of patients with LAPC ) . Overall 6-month progression-free survival ( PFS ) was 62 % , and median PFS was 10.4 months . Median overall survival ( OS ) was 11.8 months . In patients with LAPC , median OS was 9.3 months ; in patients with BRPC , median OS was 24.1 months . In the group of patients who underwent R0 resection ( all of which were R0 resections ) , median survival had not yet been reached at the time of analysis . CONCLUSIONS This regimen was well tolerated in patients with BRPC or LAPC , and almost one-third of patients underwent R0 resection . Although OS for the entire cohort was comparable to that in historical controls , PFS and OS in patients with BRPC and /or who underwent R0 resection was markedly improved PURPOSE To determine the feasibility and toxicity of delivering stereotactic radiosurgery to patients with locally advanced pancreatic cancer . METHODS AND MATERIAL S Patients with Eastern Cooperative Oncology Group performance status < or=2 and locally advanced pancreatic cancer were enrolled on this Phase I dose escalation study . Patients received a single fraction of radiosurgery consisting of either 15 Gy , 20 Gy , or 25 Gy to the primary tumor . Acute gastrointestinal toxicity was scored according to the Radiation Therapy Oncology Group criteria . Response to treatment was determined by serial high-resolution computed tomography scanning . RESULTS Fifteen patients were treated at 3 dose levels ( 3 patients received 15 Gy , 5 patients received 20 Gy , and 7 patients received 25 Gy ) . At these doses , no Grade 3 or higher acute gastrointestinal toxicity was observed . This trial was stopped before any dose-limiting toxicity was reached , because the clinical objective of local control was achieved in all 6 evaluable patients treated at 25 Gy . CONCLUSIONS It is feasible to deliver stereotactic radiosurgery to patients with locally advanced pancreatic cancer . The recommended dose to achieve local control without significant acute gastrointestinal toxicity is 25 Gy BACKGROUND To determine the safety and efficacy of neoadjuvant gemcitabine/capecitabine followed by surgery for the treatment of locally advanced pancreatic adenocarcinoma ( LAPC ) . METHODS Patients with histologically confirmed LAPC were given 3 - 6 cycles of fixed-dose rate gemcitabine/capecitabine every 3 weeks . At the end of chemotherapy , patients were restaged and underwent surgery if the disease was not classified as unresectable . Our institutional criteria were used to classify respectability , which was recategorized on the basis of National Comprehensive Cancer Network ( NCCN ) criteria retroactively . The primary end point was rate of microscopic curative resection . RESULTS Forty-three eligible patients ( 18 with borderline resectable disease and 25 with unresectable disease on the basis of NCCN criteria ) were enrolled . The radiologic response rate was 18.6 % . Grade three or worse adverse events were mainly h and -foot syndrome ( 11 % ) , and there were no grade four adverse events . Surgery was performed in 17 patients ( 39.5 % ) ; pathologic curative resection ( R0 ) was achieved in 14 patients ( 32.5 % ) among total 43 patients , and 82.3 % ( 14/17 ) among the 17 resected patients . With 43-month follow-up , the median overall was 16.6 months with a median progression-free survival of 10.0 months . Median overall survival was 23.1 months in patients who underwent surgery and 13.2 months in patients who could not complete the surgery ( P = .017 ) . CONCLUSION A subset of patients with borderline or unresectable pancreatic cancer could be performed curative tumor resection after neoadjuvant chemotherapy . Some patients might be benefit on survival from neoadjuvant chemotherapy after surgical resection Background We used a novel combination of induction chemotherapy with gemcitabine ( GEM ) and cisplatin ( CDDP ) , followed by concurrent chemoradiotherapy ( CCRT ) with the same agents in patients with locoregionally advanced pancreatic cancer . Surgery or additional chemotherapy followed on the basis of response . Methods Patients with borderline resectable or locally advanced pancreatic cancer received induction weekly with GEM ( 1000 mg/m2 ) or CDDP ( 30 g/m2 ) . Patients without progression of disease then underwent surgery or CCRT , including four cohorts of escalating GEM/CDDP doses combined with full-dose radiotherapy . After CCRT , patients deemed resectable underwent surgery ; patients with disease that remained unresectable and that did not progress received additional GEM/CDDP for 2 months . Results A mean 76 % of intended GEM dose and 75 % of CDDP dose was delivered during induction ( n = 26 ) . There were three incidences of grade 4 toxicity ( fever or neutropenia ) . After induction , five patients progressed and one patient underwent resection . Eighteen patients received CCRT , and three patients underwent resection . After CCRT , disease of 10 patients progressed , and in 5 patients , it remained unresectable without progression , and the patient received additional GEM/CDDP .  Dose-limiting toxicity was at dose level IV ( thrombocytopenia ) . Median overall and disease-specific survival was 13 months . Conclusion GEM/CDDP induction chemotherapy followed by CCRT is well tolerated and rendered the disease of 4 of 26 patients resectable in this study . The recommended phase II dose for GEM and CDDP in combination with full-dose radiotherapy ( 5040 cGy ) is 300 mg/m2 and 10 mg/m2 weekly for 5 weeks . Median survival in this group was 13 months . This neoadjuvant combined modality approach is both feasible and active ; further studies are warranted PURPOSE The primary objective of this study was to assess the 1-year survival of patients with locally advanced , unresectable pancreatic cancer treated with the combination of bevacizumab , capecitabine , and radiation . Secondary end points were toxicity , progression-free survival ( PFS ) , and response rate ( RR ) . PATIENTS AND METHODS Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m(2 ) orally twice daily on days of radiation and bevacizumab 5 mg/kg on days 1 , 15 , and 29 followed by maintenance gemcitabine 1 g/m(2 ) weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks , both in 4-week cycles until progression . Treatment plans were review ed for quality assurance ( QA ) . RESULTS Between January 2005 and February 2006 , 82 eligible patients were treated . The median and 1-year survival rates were 11.9 months ( 95 % CI , 9.9 to 14.0 months ) and 47 % ( 95 % CI , 36 % to 57 % ) . Median PFS was 8.6 months ( 95 % CI , 6.9 to 10.5 ) , and RR was 26 % . Overall , 35.4 % of patients had grade 3 or greater treatment-related gastrointestinal toxicity ( 22.0 % during chemoradiotherapy , 13.4 % during maintenance chemotherapy ) . Unacceptable radiotherapy protocol deviations ( ie , inappropriately generous volume contoured ) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy ( 45 % v 18 % ; adjusted odds ratio , 3.7 ; 95 % CI , 0.98 to 14.1 ; P = .05 ) . CONCLUSION The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine result ed in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer . Prospect i ve QA may help limit toxicity in future trials PURPOSE To provide evidence -based recommendations to practicing oncologists , surgeons , and radiation therapy clinicians to up date the 2005 clinical practice guideline on the use of sentinel node biopsy ( SNB ) for patients with early-stage breast cancer . METHODS The American Society of Clinical Oncology convened an Up date Committee of experts in medical oncology , pathology , radiation oncology , surgical oncology , guideline implementation , and advocacy . A systematic review of the literature was conducted from February 2004 to January 2013 in Medline . Guideline recommendations were based on the review of the evidence by Up date Committee . RESULTS This guideline up date reflects changes in practice since the 2005 guideline . Nine r and omized clinical trials ( RCTs ) met systematic review criteria for clinical questions 1 and 2 ; 13 cohort studies informed clinical question 3 . RECOMMENDATIONS Women without sentinel lymph node ( SLN ) metastases should not receive axillary lymph node dissection ( ALND ) .  Women with one to two metastatic SLNs planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND ( in most cases ) . Women with SLN metastases who will undergo mastectomy should be offered ALND . These three recommendation are based on RCTs . Women with operable breast cancer and multicentric tumors , with ductal carcinoma in situ ( DCIS ) who will undergo mastectomy , who previously underwent breast and /or axillary surgery , or who received preoperative/neoadjuvant systemic therapy may be offered SNB . Women who have large or locally advanced invasive breast cancer ( tumor size T3/T4 ) , inflammatory breast cancer , or DCIS ( when breast-conserving surgery is planned ) or are pregnant should not undergo SNB . These recommendations are based on cohort studies and /or informal consensus . In some cases , up date d evidence was insufficient to up date previous recommendations 4029 Background : Combination chemotherapy with gemcitabine ( GEM ) and S-1 has been reported to be promising treatment for advanced pancreatic cancer . In order to evaluate its efficacy and safety , we conducted a multicenter r and omized phase II study in patients ( pts ) with unresectable pancreatic cancer , comparing the combination of GEM and S-1 ( GS ) with GEM alone ( G ) . METHODS Eligible pts had histologically or cytologically confirmed locally advanced or metastatic pancreatic adenocarcinoma with measurable lesion . Other main inclusion criteria were an age between 20 and 80 years , no prior anticancer treatment , well preserved function of major organs and Eastern Cooperative Oncology Group ( ECOG ) PS of 0 - 2 . Pts were r and omly assigned to receive either GS or G. GS regimen consists of intravenous GEM 1,000 mg/m2 over 30 minutes on days 1 and 8 , combined with oral S-1 80 mg/m2 twice daily on days 1 - 14 , repeated every 3 weeks . On the other h and , G includes intravenous GEM 1,000 mg/m2on days 1 , 8 and 15 , repeated every 4 weeks . These therapies were continued until disease progression . The primary endpoint was objective response rate ( ORR ) . Secondary endpoints included disease control rate ( DCR ; complete response , partial response , and stable disease ) , progression-free survival ( PFS ) , overall survival ( OS ) , and safety . RESULTS Between Jun. 2007 and Aug. 2010 , 117 pts from 16 institutions were registered . Patient characteristics in GS and G were : median age ; 64.1 and 62.4 years , PS 0 ; 83 % and 77 % , locally advanced ; 23 % and 24 % , respectively . ORR of GS was 22.6 % , whereas that of G was 3.4 % . This difference was statistically significant ( p = 0.0029 ) . DCR was 60.4 % in GS and 44.1 % in G. Median PFS was 8.0 months in GS and 4.9 month in G. This was also statistically significant ( p=0.02 ) . Moreover , median OS of GS was significantly likely to be longer than that of G ( 13.0 months vs. 7.9 months ; p = 0.04 ) . The major grade 3 - 4 adverse events were neutropenia ( 24.5 % in GS and 5.1 % in G ) , thrombocytopenia ( 13.2 % in GS and 5.1 % in G ) , and skin rash ( 9.4 % in GS ) . CONCLUSIONS Our study showed the possibility that GS could be a first line therapy for unresectable pancreatic cancer . Larger r and omized phase III study is warranted OBJECTIVE This study was conducted to determine the criteria for unresectability of major peripancreatic vessels in patients with pancreatic carcinoma as revealed by optimally enhanced , pancreatic-phase thin-section helical CT . SUBJECTS AND METHODS Twenty-five patients with pancreatic adenocarcinoma who underwent local dissection during curative or palliative surgery also underwent preoperative pancreatic-phase thin-section helical CT  ( 40- to 70-sec delay , 2.5- to 3-mm collimation ) . Tumor involvement of the portal and superior mesenteric veins and the celiac , hepatic , and superior mesenteric arteries was prospect ively grade d on a 0 - 4 scale based on circumferential contiguity of tumor to vessel . Subsequent surgical results were then correlated with the CT grade s. RESULTS At surgery , definitive evaluation was possible for 80 vessels . Forty-eight of 48 vessels grade d 0 and three of three vessels grade d 1 were resectable . Four of seven vessels grade d 2 , seven of eight vessels grade d 3 , and 14 of 14 vessels grade d 4 were unresectable . A threshold of between grade s 2 and 3 , which corresponded to tumor involvement of one-half circumference of the vessel , yielded the lowest number of false-negatives and an acceptable number of false-positives for unresectability . Such a threshold would have yielded a sensitivity of 84 % , a specificity of 98 % , a positive predictive value of 95 % , and a negative predictive value of 93 % for unresectability of the vessels studied . CONCLUSION A grading system for tumor involvement of the major vessels in patients with pancreatic adenocarcinoma can be based on the degree of circumferential contiguity of tumor to vessel . Involvement of vessel to tumor that exceeds one-half circumference of the vessel is highly specific for unresectable tumor Purpose To confirm the efficacy and toxicity of gemcitabine and S-1 combination chemotherapy when used as a first-line therapy in patients with unresectable pancreatic cancer . Methods Patients with locally advanced or metastatic or recurrent pancreatic adenocarcinoma , which was histologically or cytologically proven , with at least one measurable lesion were eligible for the study .  Gemcitabine at a dose of 1,000 mg/m2 was intravenously given over 30 min on days 1 and 8 , while S-1 at a dose of 40 mg/m2 was orally given twice daily from day 1 to 14 , and the cycle was repeated every 3 weeks . The objective response rate , which was assessed according to RECIST criteria , was the primary end point . Results A total of 38 patients were enrolled between June 2006 and June 2007 . The median number of treatment courses was 5.5 ( range 1–22 ) . Thirty-four patients were evaluable for response . Although no complete response was seen , partial responses were achieved in 11 patients , result ing in an overall response rate of 32 % [ 95 % confidence interval ( CI ) 17–48 % ] . The median response duration was 6.0 months ( 95 % CI 4.6–8.3 months ) , the median time-to-progression was 5.4 months ( 95 % CI 2.9–8.0 months ) , and the median overall survival was 8.4 months ( 95 % CI 5.7–11.1 months ) . The major grade 3/4 hematologic toxicities were neutropenia ( 39.5 % ) , leukopenia ( 15.8 % ) , thrombocytopenia ( 2.6 % ) , and anemia ( 7.9 % ) . The major grade 3/4 non-hematologic toxicities included anorexia ( 10.5 % ) , stomatitis ( 2.6 % ) , rash ( 7.9 % ) , fatigue ( 7.9 % ) and hyperbilirubinemia ( 5.3 % ) . Conclusions Gemcitabine and S-1 combination chemotherapy was effective and tolerable in patients with unresectable pancreatic cancer Purpose : This phase II trial of induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation was initiated to determine the activity of this regimen in patients with unresectable pancreatic cancer . Methods : Patients with locally advanced , nonmetastatic adenocarcinoma of the pancreas received 2 cycles of induction irinotecan ( 100 mg/m2 IV ) and gemcitabine ( 1000 mg/m2 IV ) on days 1 and 8 of each 3-week cycle . Following the induction , patients without disease progression received gemcitabine administered twice weekly ( 40 mg/m2/day ) for 5 weeks concurrent with upper abdominal radiation ( 50.4 Gy over 5.5 weeks ) . Results : From April 2000 to August 2003 , 20 patients were entered into this study , 17 of whom were evaluable for treatment response . Characteristics included a median age of 67 years ( range , 44–87 years ) and 14 men ( 70 % ) .  Grade s III and IV hematologic toxicity occurred in 25 % and 5 % of patients respectively and was primarily thrombocytopenia . No grade IV gastrointestinal toxicities or deaths due to therapy were observed . All therapy was completed in 8 patients , 7 patients were removed due to progression , 2 due to  toxicity  , 2 refused further treatment , and 1 was removed per the treating physician . The median time to progression and median survival was 5.1 months ( 95 % CI , 3.2–6.7 ) and 8.8 months ( 95 % CI , 6.4–10.1 ) respectively . Four patients ( 20 % ) were alive at 12 and 18 months . Conclusion : Induction irinotecan/gemcitabine followed by twice-weekly gemcitabine and upper abdominal radiation is feasible in patients with locally advanced pancreatic cancer . This regimen , however , has only modest activity and should not be explored further PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies . Pre clinical and early clinical evidence has supported targeting the epidermal growth factor receptor ( EGFR ) signaling pathway in patients with pancreas cancer . This trial was conducted to evaluate the contribution of an EGFR-targeted agent to st and ard gemcitabine therapy . Cetuximab is a monoclonal antibody against the lig and -binding domain of the receptor . PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were r and omly assigned to receive gemcitabine alone or gemcitabine plus cetuximab . The primary end point was overall survival . Secondary end points included progression-free survival , time to treatment failure , objective response , and toxicity . RESULTS A total of 745 eligible patients were accrued . No significant difference was seen between the two arms of the study with respect to the median survival time ( 6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm ; hazard ratio = 1.06 ; 95 % CI , 0.91 to 1.23 ; P = .23 , one-sided ) . Objective responses and progression-free survival were similar in both arms of the study . Although time to treatment failure was longer in patients on gemcitabine plus cetuximab ( P = .006 ) , the difference in length of treatment was only 2 weeks longer in the combination arm . Among patients who were studied for tumoral EGFR expression , 90 % were positive , with no treatment benefit detected in this patient subset . CONCLUSION In patients with advanced pancreas cancer , the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone . Alternate targets other than EGFR should be evaluated for new drug development
Initial systemic chemotherapy ( 6 months ) with a combination regimen is recommended for most patients ( for some patients radiation therapy may be offered up front ) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile .
There is no clear evidence to support one regimen over another .
PURPOSE To provide evidence -based recommendations to oncologists and others for treatment of patients with locally advanced , unresectable pancreatic cancer .