Extended Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer Demonstrates Promising Postoperative Outcomes and Survival Neoadjuvant Chemotherapy with Gemcitabine and S-1 for Resectable and Borderline Pancreatic Ductal Adenocarcinoma: Results from a Prospective Multi-institutional Phase 2 Trial Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. A Single-Arm, Nonrandomized Phase II Trial of Neoadjuvant Gemcitabine and Oxaliplatin in Patients With Resectable Pancreas Adenocarcinoma Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. Role of neoadjuvant concurrent chemoradiation in locally advanced unresectable pancreatic cancer: a feasibility study at tertiary care centre. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic response.
Background The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined . Herein we report the outcomes of an extended neoadjuvant chemotherapy regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head . Methods Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospect ively maintained registry . Included patients were initiated on a 24-week course of neoadjuvant chemotherapy .  Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent . Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed . Results Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy . Thirty-nine ( 61 % ) met resection criteria and underwent operative exploration with curative intent , and 31 ( 48 % ) were resected . Of the resected patients , 18 ( 58 % ) had positive lymph nodes , 15 ( 48 % ) required en-bloc venous resection , 27 ( 87 % ) had a R0 resection , and 3 ( 10 % ) had a complete pathologic response . There were no postoperative deaths at 90 days , 16 % of patients had a severe complication , and the 30-day readmission rate was 10 % . The median overall survival of all 64 patients was 23.6 months , whereas that of unresectable patients was 15.4 months . Twenty-five of the resected patients ( 81 % ) are still alive at a median follow-up of 21.6 months . Conclusions Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma , selects a subset of patients for curative surgery with low perioperative morbidity , and is associated with favorable survival Background Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma ( PDAC ) , but recurrence rates are high even after purported curative resection . First-line treatment with gemcitabine and S-1 ( GS ) is associated with promising antitumor activity with a high response rate . The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting . Methods In a multi-institutional single-arm phase 2 study , neoadjuvant chemotherapy ( NAC ) with gemcitabine and S-1 , repeated every 21 days , was administered for two cycles ( NAC-GS ) to patients with resectable and borderline PDAC . The primary end point was the 2-year survival rate . Secondary end points were feasibility , resection rate , pathological effect , recurrence-free survival , and tumor marker status . Results Of 36 patients enrolled , 35 were eligible for this clinical trial conducted between 2008 and 2010 . The most common toxicity was neutropenia in response to 90 % of the relative dose intensity . Responses to NAC included radiological tumor shrinkage ( 69 % ) and decreases in CA19 - 9 levels ( 89 % ) . R0 resection was performed for 87 % in resection , and the morbidity rate ( 40 % ) was acceptable . The 2-year survival rate of the total cohort was 45.7 % . Patients who underwent resection without metastases after NAC-GS ( n = 27 ) had an increased median overall survival ( 34.7 months ) compared with those who did not undergo resection ( P = 0.0017 ) . Conclusions NAC-GS was well tolerated and safe when used in a multi-institutional setting . The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC BACKGROUND Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma ( PDAC ) but no st and ard of care exists . Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging pre clinical activity in PDAC . We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy ( IMRT ) as neoadjuvant therapy in patients with localized or locally advanced PDAC . EXPERIMENTAL DESIGN Treatment consisted of cetuximab load at 400 mg/m(2 ) followed by cetuximab 250 mg/m(2 ) weekly and gemcitabine 50 mg/m(2 ) twice-weekly given concurrently with IMRT to 54 Gy . Following therapy , patients were considered for resection . RESULTS Thirty-seven patients were enrolled with 33 assessable for response . Ten patients ( 30 % ) manifested partial response and 20 ( 61 % ) manifested stable disease by RECIST . Twenty-five patients ( 76 % ) underwent resection , including 18/23 previously borderline and 3/6 previously unresectable tumors . Twenty-three ( 92 % ) of these had negative surgical margins . Pathology revealed that 24 % of resected tumors had grade III/IV tumor kill , including two pathological complete responses ( 8 % ) . Median survival was 24.3 months in resected patients . Outcome did not vary by epidermal growth factor receptor status . CONCLUSIONS Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC . Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival . Pathological complete responses can occur . This combination warrants further investigation Background In nonr and omized trials , neoadjuvant treatment was reported to prolong survival in patients with pancreatic cancer . As neoadjuvant chemoradiation is established for the treatment of rectal cancer we examined the value of neoadjuvant chemoradiotherapy in pancreatic cancer in a r and omized phase II trial . Radiological staging defining resectability was basic information prior to r and omization in contrast to adjuvant therapy trials resting on pathological staging . Patients and methods Patients with resectable adenocarcinoma of the pancreatic head were r and omized to primary surgery ( Arm A ) or neoadjuvant chemoradiotherapy followed by surgery ( Arm B ) , which was followed by adjuvant chemotherapy  in both arms . A total of 254 patients were required to detect a 4.33-month improvement in median overall survival ( mOS ) . Results The trial was stopped after 73 patients ; 66 patients were eligible for analysis . Twenty nine of 33 allocated patients received chemoradiotherapy . Radiotherapy was completed in all patients . Chemotherapy was changed in 3 patients due to toxicity . Tumor resection was performed in 23 vs. 19 patients ( A vs. B ) . The R0 resection rate was 48 % ( A ) and 52 % ( B , P = 0.81 ) and (y)pN0 was 30 % ( A ) vs. 39 % ( B , P = 0.44 ) , respectively . Postoperative complications were comparable in both groups . mOS was 14.4 vs. 17.4 months ( A vs. B ; intention-to-treat analysis ; P = 0.96 ) . After tumor resection , mOS was 18.9 vs. 25.0 months ( A vs. B ; P = 0.79 ) . Conclusion This worldwide first r and omized trial for neoadjuvant chemoradiotherapy in pancreatic cancer showed that neoadjuvant chemoradiation is safe with respect to toxicity , perioperative morbidity , and mortality . Nevertheless , the trial was terminated early due to slow recruiting and the results were not significant . IS RCT N78805636 ; NCT00335543.ZusammenfassungHintergrundMehrere nichtr and omisierte Studien zeigten , dass eine neoadjuvante Therapie das Überleben bei Patienten mit Pankreaskarzinom verlängert . Beim lokal fortgeschrittenen Rektumkarzinom gehört die neoadjuvante Radiochemotherapie bereits zum Therapiest and ard . Analog wurde der Stellenwert einer Radiochemotherapie beim Pankreaskarzinom in einer r and omisierten Phase-II-Studie untersucht . Das prätherapeutische radiologische Staging war Grundlage dieser Studie i m Gegensatz zu adjuvanten Therapiestudien , die auf pathohistologischem Staging basieren . Patienten und Method enPatienten mit resektablem Pankreaskopfkarzinom wurden r and omisiert in primäre Operation ( Arm A ) versus neoadjuvante Radiochemotherapie gefolgt von einer Operation ( Arm B ) . Beide Gruppen erhielten eine adjuvante Chemotherapie . Es waren 254 Patienten erforderlich , um eine Verbesserung des medianen Gesamtüberlebens von 4,33 Monaten zu erfassen . ErgebnisseDie Studie wurde wegen zögerlicher Rekrutierung nach Einschluss von 73 Patienten beendet . Insgesamt konnten 66 Patienten ausgewertet werden . Die ihnen zugeordnete Radiochemotherapie erhielten 29 von 33 Patienten . Alle Patienten bekamen die vollständige Bestrahlungstherapie . Wegen der Toxizität wurde bei 3 Patienten die Chemotherapie reduziert . Eine Pankreastumorresektion erhielten 23 vs. 19 Patienten ( A vs. B ) . Die R0-Resektionsrate betrug 48 % ( A ) und 52 % ( B , P = 0,81 ) . Bei 30 % ( A ) versus 39 % ( B , P = 0,44 ) der resezierten Patienten waren keine Lymphknotenmetastasen vorh and en . Die postoperativen Komplikationen waren in beiden Gruppen vergleichbar . Das mediane Gesamtüberleben betrug 14,4 vs. 17,4 Monate ( A vs. B ; „ Intention-to-treat“-Analyse ; P = 0,96 ) . Nach Pankreastumorresektion stieg das Gesamtüberleben auf 18,9 vs. 25,0 Monate ( A vs. B ; P = 0,79).SchlussfolgerungDiese weltweit erste r and omisierte Studie zur neoadjuvanten Radiochemotherapie beim Pankreaskopfkarzinom war in Bezug auf Toxizität sowie perioperative Morbidität und Mortalität gut durchführbar . Die Ergebnisse sind jedoch nicht signifikant , da diese r and omisierte Studie vorzeitig wegen mangelnder Rekrutierung beendet werden musste . IS RCT N78805636 ; NCT00335543 Background Survival after surgery for pancreas cancer remains low . This improves with adjuvant chemotherapy , but up to 30 % patients do not receive the prescribed treatment . Neoadjuvant therapy may increase the proportion of patients who receive all treatment components , may downstage disease before surgery , and may provide early treatment of micrometastases . This r and omized phase 2 study compares gemcitabine-based chemotherapy regimens to identify the most promising regimen for future study . Methods Fifty patients with potentially resectable pancreas lesions were enrolled onto the study . Twenty-four patients were r and omized to gemcitabine ( 1000 mg/m2 ) every 7 days for 43 days ; 26 patients were r and omized to gemcitabine ( 1000 mg/m2 ) and cisplatin ( 25 mg/m2 ) , 7 to the original schedule ( omitting day 22 ) and 19 to a revised schedule due to neutropenia ( omitting days 15 and 36 ) . The primary outcome measure was resection rate . Results Patients who were allocated to gemcitabine received a median of 85 % of the planned dose . Patients who were allocated to combination treatment received a median of 88 % and 92 % of the planned gemcitabine and cisplatin doses , respectively . There were 10 episodes of grade III/IV hematological toxicity in each group . Twenty-seven patients ( 54 % ) underwent pancreatic resection , 9 ( 38 % ) in the gemcitabine arm and 18 ( 70 % ) in the combination arm , with no increase in surgical complications . To date , 34 patients ( 68 % ) have died . Twelve-month survival for the gemcitabine and combination groups was 42 % and 62 % . Conclusions Chemotherapy can be safely administered before pancreatic surgery . Combination therapy with gemcitabine and cisplatin is associated with a high resection rate and an encouraging survival rate , suggesting that further study is warranted PURPOSE To test the safety of neoadjuvant chemotherapy for resectable pancreatic cancer . PATIENTS AND METHODS Patients with cytologically proven resectable adenocarcinoma of the pancreatic head were eligible for this prospect i ve phase II trial . After confirmation of resectability by contrast-enhanced computed tomography ( ceCT ) , positron emission tomography/CT , laparoscopy , and endoscopic ultrasound , patients received four biweekly cycles of gemcitabine 1,000 mg/m(2 ) and cisplatin 50 mg/m(2 ) . Thereafter , staging was repeated and patients underwent surgery .  Quality of life ( QoL ) and prealbumin serum levels were determined pre- and postchemotherapy . Follow-up included 3-month CA 19 - 9 measurements and ceCT after 6 , 12 , 18 , and 24 months . Histologic tumor response was assessed by two scoring systems . RESULTS Twenty-eight patients entered this study .  Adverse effects were mainly gastrointestinal and hematologic , most often mild , and never of grade 4 . Twenty-six patients ( 93 % ) had resectable cancer on restaging examinations , and the R0 resection rate was 80 % . Histologic tumor response and cytopathic effects were documented in 54 % and 83 % of patients , respectively . On intention-to-treat analysis , disease-free and overall survival were 9.2 months ( 95 % CI , 5.6 to 12.9 months ) and 26.5 months ( 95 % CI , 11.4 to 41.5 months ) and 9 months ( 95 % CI , 6.99 to 10.1 months ) and 19.1 months ( 95 % CI , 15 to 23.1 months ) for ductal adenocarcinoma , respectively . QoL improved in two items and was unchanged in all other items . Moreover , prealbumin serum levels significantly improved during chemotherapy ( P = .008 ) . CONCLUSION Neoadjuvant chemotherapy with gemcitabine and cisplatin is well tolerated and does not impair resectability of pancreatic cancer . Furthermore , it improves the QoL and the nutritional status of affected patients with favorable overall and disease-free survival Background : The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined . Objective : We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma . Methods : Eligible patients were screened using  computed tomography – pancreas angiography , laparoscopy , endoscopic ultrasonography , and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m2 intravenously over 100 minutes and oxaliplatin 80 mg/m2 intravenously over 2 hours , every 2 weeks . Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine ( 1000 mg/m2 intravenously over 30 minutes days 1 , 8 , and 15 every 4 weeks ) . The primary endpoint was 18-month overall survival and secondary endpoints included radiological , tumor marker and pathological response to neoadjuvant therapy , time to recurrence , patterns of failure , and feasibility of obtaining preoperative core biopsies . Results : Thirty-five of 38 patients ( 92 % ) completed neoadjuvant therapy . Twenty-seven patients underwent tumor resection ( resectability rate 71 % ) , of which 26 initiated adjuvant therapy for a total of 23 patients ( 60.5 % ) who completed all planned therapy . The 18-month survival was 63 % ( 24 patients alive ) . The median overall survival for all 38 patients was 27.2 months ( 95 % confidence interval : 17–NA ) and the median disease-specific survival was 30.6 months ( 95 % confidence interval : 19–NA ) . Conclusions : This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma . Improved patient selection and more active systemic regimens are key . Clinical trials identification : NCT00536874 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 PURPOSE A r and omized phase II trial ( E1200 ) was design ed to assess toxicities and surgical resection rates in two neoadjuvant gemcitabine-based chemoradiation regimens in patients with borderline resectable pancreatic cancer . The trial was terminated early due to poor accrual . PATIENTS AND METHODS Patients with borderline resectable adenocarcinomas of the pancreas were enrolled . Arm A patients ( n = 10 ) received gemcitabine 500 mg/m(2 ) IV weekly for 6 weeks , with radiation to 50.4 Gy followed by surgical resection . Arm B patients ( n = 11 ) received preoperative gemcitabine 175 mg/m(2 ) on days 1 , 5 , 29 , and 33 , cisplatin 20 mg/m(2 ) on days 1 - 5 and 29 - 32 , 5-FU 600 mg/m(2 ) on days 1 - 5 and 29 - 32 , followed by radiation with continuous infusion 5-FU 225 mg/m(2 ) for 6 weeks . All patients received adjuvant gemcitabine 1,000 mg/m(2 ) weekly x 3 for five cycles . RESULTS Three patients in arm A , and two patients in arm B were resected . Hematologic toxicity was comparable between the two arms except more patients in arm B developed grade 3 or 4 thrombocytopenia than those in arm A. Arm B had fewer grade 1 - 2 GI toxicities although more patients ( 45 % ) experienced grade 3 - 4 GI toxicity . CONCLUSIONS This phase II trial showed that both regimens were tolerable , and resectability and survival were comparable to previous studies 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 PURPOSE To assess the safety and efficacy of a new neoadjuvant chemoradiation ( CRT ) docetaxel-based regimen in patients with resectable adenocarcinoma of the pancreatic head or body . PATIENTS AND METHODS 34 patients with histologically-confirmed resectable pancreatic adenocarcinoma were included in this prospect i ve two-center phase II study . Radiotherapy was delivered at the dose of 45 Gy in 25 fractions of 1.8 Gy per fractions , 5 days/week , over 5 weeks . Docetaxel was administered as a 1-h intravenous ( IV ) infusion repeated every week during 5 weeks . The dose was 30 mg/m(2)/week . All patients were restaged after completion of CRT . RESULTS Tumor progression was documented in 11 patients ( 32 % ) , stable disease was documented in 20 patients ( 59 % ) , and partial remission was documented in 3 patients ( 9 % ) . 23 patients still with local disease at restaging underwent explorative laparotomy . Of this , 17 patients ( 50 % ) had a curative pancreaticoduodenectomy with lymphadenectomy . Morbidity and mortality rates were 29 % and 0 % , respectively . Three patients ( 17 % ) had complete histological responses and 5 patients had minimal residual disease . All resected patients ( n = 17 ) underwent R0 resection . The median and five-year survival times for the resected patients were 32 months and 41 % , respectively . Among the resected patients , ten ( 59 % ) died as a result of recurrent pancreatic cancer without local tumor bed recurrence . CONCLUSIONS Neoadjuvant docetaxel-based chemoradiation is well-tolerated . Resected patients had a prolonged survival time . Further studies are needed to confirm our findings and determine the role of such a neoadjuvant approach
Neoadjuvant treatment in non-metastatic pancreatic cancer ( PaC ) has the theoretical advantages of downstaging the tumor , sterilizing any present systemic undetectable disease , selecting patients for surgery and administering therapy to each patient .