Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer? Preoperative versus postoperative chemoradiation for patients with resected pancreatic adenocarcinoma. Survival after combined modality therapy for pancreatic cancer. Impact of preoperative chemoradiotherapy on survival in patients with resectable pancreatic cancer. Chemoradiotherapy in the Treatment of Regional Pancreatic Carcinoma: A Phase II Study Preoperative chemoradiation in adenocarcinoma of the pancreas. A single centre experience advocating a new treatment strategy. Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma [Locally advanced pancreatic adenocarcinoma. Chemoradiotherapy, reevaluation and secondary resection]. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study.
Background . The optimal care for patients with unresectable , non-metastatic pancreatic adenocarcinoma ( PAC ) is debated . We treated 17 consecutive cases with preoperative radiochemotherapy ( RCT ) as a means for downstaging their tumours and compared outcome with 35 patients undergoing direct surgery for primarily resectable PAC during the same time period . Methods . The patients had biopsy proven , unresectable , non-metastatic PAC which engaged ≥50 % of the circumference of a patent mesenteric/portal vein for a distance ≥2 cm and /or < 50 % of the circumference of a central artery for < 2 cm . The preop therapy included two courses of Xelox ( oxaliplatin 130 mg/m2 d1 ; capecitabine 2 000 mg/m2 d1–14 q 3 w ) followed by 3-D conformal radiotherapy ( 50.4 Gy ; 1.8 Gy fractions ) with reduced Xelox ( d1 - 5 q 1 w X 6 ) . Results . No incident of RCT -related CTC Grade 3–4 haematologic and six cases of non-haematologic side-effects were diagnosed . Sixteen patients completed the RCT and were rescanned with CT and reevaluated for surgery 4 weeks post- RCT . Five cases were diagnosed with new metastases to the liver . Eleven patients were accepted for surgery whereof eight underwent a curative R0-resection . The median overall survival for the latter group was 29 months , which compared favourably with our control group of patients undergoing direct curative surgery for primarily resectable PAC ( median OS : 16 months ; RO-rate : 75 % ) . Perioperative morbidity was similar in the two cohorts but the duration of surgery was longer ( 576 vs. 477 min ) and the op blood loss was greater ( 3288 vs. 1460 ml ) in the RCT -cohort ( p < 0.05 ) . The 30-day mortality was zero in both groups . Conclusion . Preoperative RCT in patients with locally advanced PAC result ed in a high rate of curative resections and promising median survival in our treatment series . This trimodality approach merits further exploration in new studies , which are currently underway at our Department 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 Two groups of patients with adenocarcinoma of the pancreas treated with either preoperative chemoradiation ( preop CTRT ) or postoperative chemoradiation ( postop CTRT )  were retrospectively analyzed for various treatment-related parameters . Between November 1986 and October 1996 , a total of 70 patients with pancreatic adenocarcinoma were enrolled into preop CTRT protocol s at our institution . Twenty-five patients with adenocarcinoma of the head of the pancreas underwent pancreaticoduodenectomy with curative intent .  After the closure of the preop CTRT protocol s , we had the opportunity to perform 23 pancreatic resections without preop CTRT . After surgery , these patients were advised to undergo CTRT . These two groups of patients were therefore selected consecutively , dependent only on the time of referral and no other bias . These two cohorts of patients are compared for various intraoperative parameters , length of hospital stay , pathologic findings , time to recurrence , and survival .  Mean age was 65 and 66 years in the preop and postop CTRT groups , respectively . Sex distribution was almost equal . Treatment breaks result ing in greater than 1 week delay in the radiotherapy occurred in 2 ( 8 % ) of 25 patients in the preop CTRT group ( myelotoxicity in 1 case and biliary sepsis in 1 case ) , whereas no treatment breaks > 1 week occurred in those receiving postop CTRT . Eleven patients in preop CTRT had grade 3 or 4 toxicity , whereas none was noted in those with postop CTRT . There was one postoperative death in the preop CTRT group and none in the postop CTRT group . Mean time to the start of CTRT was 45 days ( range , 20 - 66 days ) after pancreaticoduodenectomy . Delay of > 60 days to the onset of CTRT occurred in 2 ( 22 % ) patients and was attributable to patient delays in time to recover from surgery or patient noncompliance . Furthermore , 5 of 23 patients ( 22 % ) in the postop CTRT group did not receive treatment for various reasons . Average estimated operative blood loss was 1933 mL ( median 1550 ) and 1060 mL ( median 1000 ) for preop and postop CTRT groups , respectively . Mean length of operation was 488 minutes ( median 480 ) and 486 minutes ( median 480 ) . Median length of postoperative stay was 22 and 20 days ( ranges , 9 - 144 and 10 - 38 ) . Pathological findings in the resected specimens showed significantly fewer involved nodes in the preop CTRT group ( 28 vs 87 % ; P = 0.0006 ) , whereas similar numbers of nodes/patient were counted in each group ( 14 vs 22 , P = 0.11 ) . More negative resection margins were observed in the preop CTRT group ( 28 vs 56 % ; P = not significant ) . A significantly greater amount of fibrosis replacing the tumor was observed in the preop CTRT group ( 70 vs 40 % ; P = 0.0001 ) . There were no significant survival differences observed ( median 20 months vs 25 months ; P = 0.48 ) , in follow-up that ranged from 4 to 76 months ( median 44 months for surviving patients ) for the preop group and 4 to 40 months ( median 16 months for surviving patients ) for those with postop CTRT . Local failure either alone or as a component of distant failure occurred in 16 per cent ( 4 of 25 patients ) with preop CTRT and 16.6 per cent ( 3 of 18 ) with postop CTRT . Analysis of differences between those treated with preoperative and postoperative CTRT demonstrates similarity in toxicity and effects . However , 22 per cent of patients intended for postoperative therapy did not receive treatment 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 AIM To explore whether preoperative chemoradiation therapy improves survival of patients with pancreatic cancer undergoing resectional surgery .  METHODS Forty-seven patients with a malignant pancreatic tumor localized in the head or uncinate process of the pancreas underwent radical pancreatico-duodenectomy .  Twenty-two received chemoradiation therapy ( gemcitabine and radiation dose 50.4 Gy ) before surgery ( CRR ) and 25 patients underwent surgery only ( RO ) . The study was non-r and omised . Patients were identified from a prospect i ve data base . RESULTS The median survival time was 30.2 mo in the CRR group and 35.9 mo in the RO group . No statistically significant differences were found in subclasses according to lymph node involvement , TNM stages , tumor size , or perineural invasion . The one , three and five year survival rates were 81 % , 33 % and 33 % , respectively , in the CRR group and 72 % , 47 % and 23 % , respectively , in the RO group . In ductal adenocarcinoma , the median survival time was 27 mo in the CRR group and 20 mo in the RO group . No statistically significant differences were found in the above subclasses . The one , three and five year survival rates were 79 % , 21 % and 21 % , respectively , in the CRR group and 64 % , 50 % and 14 % , respectively , in the RO group . The overall hospital mortality rate was 2 % . The morbidity rate was 45 % in the CRR group and 32 % ( NS ) in the RO group . CONCLUSION Major multicenter r and omized studies are needed to conclusively assess the impact of neoadjuvant treatment in the management of pancreatic cancer In locally advanced pancreatic cancer , the utilization of chemotherapy and radiotherapy is increasing , although in view of the reported long-term results of several contemporary trials , further improvements are certainly needed . Encouraging results using the combination of cisplatin , cytarabine , caffeine , and continuous infusion ( CI ) 5-fluorouracil ( 5-FU ) ( PACE ) for the treatment of advanced pancreatic carcinoma prompted a phase II study using PACE followed by external beam radiotherapy with CI of 5-FU ( PACE-RT ) for localized disease . Forty-one patients were treated with PACE-RT as adjuvant therapy after surgical resection ( 21 patients ) , or as primary therapy for locally advanced , unresectable disease ( 20 patients ) , with reevaluation for resection after completion of treatment . PACE consisted of cisplatin 100 mg/m2 IV on day 1 , cytarabine 2 g/m2 IV every 12 hours × 2 doses , and caffeine 400 mg/m2 subcutaneously after each cytarabine dose ; and days 3 to 21 , 5-FU 250 mg/m2/d given by CI . Cycles were repeated every 28 days . After 2 cycles of PACE , radiation therapy was given concurrently with 5-FU at 200 mg/m2/d . In the adjuvant setting , the tumor bed and the draining lymph node basin received 50.4 Gy and 45 Gy , respectively . In the neoadjuvant setting , the primary and regional lymph nodes were to receive 39.6 Gy followed by a neutron boost of 8 NGy to the gross tumor volume . Photon therapy was delivered at 1.8 Gy per fraction and neutron therapy at 0.8 NGy per fraction , 5 days a week . All patients were evaluable for toxicity and survival . The most common toxicity was myelosuppression , with grade III to IV neutropenia occurring in 59 % of the patients . The median survival times in the locally advanced and adjuvant patients were 13.4 and 18.1 months , with 1-year survival rates of 52 % and 65 % , respectively . Nine of 20 patients receiving PACE-RT for unresectable carcinoma had sufficient tumor regression to meet clinical criteria for exploration ; three were resected with curative intent . The survival of these three patients undergoing resection after neo-adjuvant therapy was 22.4 , 24.3 and 40 months . The treatment program was active , but only moderately well tolerated . Modification of this regimen with newer , less toxic drugs may provide better results and reduced toxicity AIMS To evaluate a single centre 's experience with pancreatic carcinoma focused on preoperative chemoradiation therapy ( CRT ) for treatment of locally advanced pancreatic carcinoma . The aim of the present analysis was to evaluate the median overall survival time ( OS ) after preoperative CRT and to compare it with OS after primary resection of pancreatic carcinoma . In conclusion a new treatment strategy was developed using multimodality treatment for pancreatic carcinoma deemed to be resectable by CT-scan . PATIENTS AND METHODS Between 1995 and 2003 , 302 patients with ductal adenocarcinoma of the pancreatic head and body were recorded prospect ively and OS was analysed with regard to therapy . RESULTS Fifty-eight patients were resected without any pretreatment and had an OS of 21 months . Twenty-one patients with initially unresectable tumours underwent CRT followed by resection and had an OS of 54 months , which was not significantly different from primary resection ( p=0.315 ) . Lymph node metastasis was significantly reduced after CRT ( p=0.0029 ) . OS for patients whose tumours could not be resected was 3 - 10 months , depending on tumour stage and consecutive therapy . CONCLUSION CRT pretreatment was effective in locally advanced pancreatic carcinoma and result ed in resection of tumours otherwise staged as non-resectable . This experience led to a r and omized trial for patients who by CT are staged to have resectable cancer of the pancreatic head with the intent to increase curative resectability and survival by neoadjuvant CRT ( IS RCT N78805636/NCT00335543 ) Resection of pancreatic carcinoma is re source ‐intensive with a limited impact on survival . Chemotherapy and /or radiotherapy ( RT ) have been shown to be effective palliation . To examine whether preoperative chemoradiotherapy as the initial treatment improves survival for patients with a regional pancreatic adenocarcinoma with a minimal chance of being resected successfully , an outcomes trial was conducted UNLABELLED Induction chemoradiotherapy ( CRT ) may downstage locally advanced pancreatic tumors but secondary resections are unfrequent . However some responders ' patients may benefit of a R0 resection . PATIENTS AND METHODS We report 18 resections among 29 locally advanced pancreatic cancers ; 15 patients were treated with neoadjuvant 5-FU-cisplatin based ( 13 ) or taxotere based ( 2 patients ) chemoradiotherapy ( 45 Gy ) , and 3 patients without histologically proven adenocarcinoma were resected without any preoperative treatment . RESULTS The morbidity rate was 28 % and the mortality rate was 7 % ; one patient died after resection ( 5.5 % ) and one died after exploration ( 9 % ) . The R0 resection rate was 50 % . The median survival for the resected patients was not reached and the actuarial survival at 3 years was 59 % . Two specimens showed no residual tumor and the two patients were alive at 15 and 46 months without recurrence ; one specimen showed less than 10 % viable tumoral cells and the patient was alive at 36 months without recurrence . A mesenteric infa rct ion was the cause of a late death at 3 years in a disease free patient ( radiation induced injury of the superior mesenteric artery ) . The median survival of the 11 non-resected patients was 21 months and the actuarial survival at 2 years was 0 % . When the number of the resected patients ( 18 ) was reported to the entire cohort of the patients with locally advanced pancreatic cancer treated during the same period in our institution , the secondary resectability rate was 9 % . CONCLUSION Preoperative chemoradiotherapy identifies poor surgical c and i date s through observation and may enhance the margin status of patients undergoing secondary resection for locally advanced tumors . However it remains difficult to evaluate the results in the literature because of the variations in the definitions of resectability . The best therapeutic strategy remains to be defined , because the majority of patients ultimately succumb with distant metastatic disease R and omized trials of the Gastrointestinal Tumor Study Group have previously demonstrated enhanced survival of patients with locally unresectable pancreatic cancer treated with  5-fluorouracil in combination with radiation therapy compared with that of patients treated with radiation therapy alone  . The present study compared the survival of patients treated with  multidrug chemotherapy [ streptozocin , mitomycin , and 5-fluorouracil ( SMF ) ] versus radiation combined with 5-fluorouracil followed by the same three-drug SMF combination . In 43 patients r and omly allocated between these two arms , an improved median survival for the combined-modality therapy ( 42 weeks ) compared with chemotherapy alone ( 32 weeks ) was demonstrated . Overall survival following this combined-modality treatment program ( 41 % at 1 year ) was significantly superior to that following SMF chemotherapy alone ( 19 % at 1 year ) , by a two-tailed log rank test ( P less than .02 ) . Serial studies of the Gastrointestinal Tumor Study Group with patients with locally unresectable pancreatic adenocarcinoma have shown that combined-modality therapy is superior to either optimal radiotherapy or chemotherapy alone BACKGROUND The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer ( LAPC ) is uncertain . PATIENTS AND METHODS One hundred and nineteen patients with LAPC , World Health Organization performance status of zero to two were r and omly assigned to either the induction CHRT group ( 60 Gy , 2 Gy/fraction ; concomitant 5-fluorouracil infusion , 300 mg/m(2)/day , days 1 - 5 for 6 weeks ; cisplatin , 20 mg/m(2)/day , days 1 - 5 during weeks 1 and 5 ) or the induction gemcitabine group ( GEM : 1000 mg/m(2 ) weekly for 7 weeks ) . Maintenance gemcitabine ( 1000 mg/m(2 ) weekly , 3/4 weeks ) was given in both arms until disease progression or toxicity . RESULTS Overall survival was shorter in the CHRT than in GEM arm [ median survival 8.6 ( 99 % confidence interval 7.1 - 11.4 ) and 13 months ( 8.7 - 18.1 ) , P = 0.03 ] . One-year survival was , respectively , 32 % and 53 % . These results were confirmed in a per- protocol analysis for patients who received 75 % or more of the planned dose of radiotherapy . More overall grade s 3 - 4 toxic effects were recorded in the CHRT arm , both during induction ( 36 versus 22 % ) and maintenance ( 32 versus 18 % ) . CONCLUSION This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone
Introduction This systematic review and meta- analysis aims to characterize the surgically important benefits and complications associated with the use of neoadjuvant chemoradiotherapy for the treatment of both resectable and initially unresectable pancreatic cancer .