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Adjuvant chemotherapy and outcomes in patients with nodal and resection margin-negative pancreatic ductal adenocarcinoma: A systematic review and meta-analysisNicola Flaum MbBCh BSc MRCP1, Richard A Hubner MA BM BCh MRCP PhD1, Juan W Valle MB ChB MSc FRCP1,2, Eitan Amir MB ChB PhD3, Mairéad G McNamara MB BCh BAO B Med Sci BSC PhD MRCP1,21 – Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom2 – Division of Cancer Sciences, University of Manchester, United Kingdom3 – Department of Medical Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, CanadaCorresponding Author Dr Mairéad G McNamaraDepartment of Medical OncologyThe Christie NHS Foundation TrustWilmslow RoadWithington ManchesterUnited KingdomM20 4BXMairead.McNamara@christie.nhs.ukTel:+44 161 446 8106Fax:+44 161 446 8565Co-authors email addresses:nicola.flaum@christie.nhs.ukRichard.hubner@christie.nhs.ukJuan.valle@christie.nhs.ukEitan.Amir@uhn.caNo additional funding was received for this work.No additional disclosures.SynopsisAdjuvant chemotherapy (AC) following pancreatic carcinoma (PC) resection improves overall survival (OS). This systematic review and meta-analysis looked at influence of nodal and resection status. While there was greater survival benefit in patients PS 0 and with body/tail tumours, there was a non-significant effect in N- vs N+ patients on OS and no difference between R0 and R1 patients. AbstractAdjuvant chemotherapy (AC) following pancreatic carcinoma (PC) resection improves overall survival (OS). A systematic review identified 10 phase-2/3 studies investigating AC in 3644 patients looking at the influence of nodal and resection status. AC significantly improved DFS, OS and 5-year odds of death risk. There was greater survival benefit in patients PS 0 and with body/tail tumors. There was a non-significant effect in N-/N+ patients on OS and no difference between R0/R1 patients.Keywords: pancreatic cancer, meta-analysis, systematic review, adjuvant chemotherapy, resection margin, lymph nodesINTRODUCTIONPancreatic cancer remains one of the most lethal malignancies worldwide. However, survival is modestly improving, with a five-year survival rate of 8.2% compared with <4% before 20001. In 2017, it was estimated that it will be the 12th commonest cancer, occurring in 53,670 people, but will be the third highest cause of cancer-related death, after lung and colorectal cancer, causing an estimated 43,090 deaths1. Surgery is the only curative treatment, but only a minority of patients present with resectable disease2,3. In patients with pancreatic ductal adenocarcinoma (PDAC) for whom surgery is an option, the role of adjuvant therapy was first investigated in the 1980s. The Gastrointestinal Tumor Study Group (GITSG) allocated 43 patients to adjuvant chemoradiotherapy or surgery alone, and reported a 9 month benefit in overall survival (OS) of chemoradiotherapy versus surgery alone (20 vs 11 months)4. The first phase III trial investigating the role of adjuvant chemotherapy and chemoradiotherapy in patients with resected PDAC was the European Study Group for Pancreatic Cancer 1 (ESPAC 1) trial, which involved 289 patients, and reported a significant benefit from addition of adjuvant chemotherapy (leucovorin 20mg/m2 and 5-Fluorouracil 425mg/m2) post-surgery (five-year survival 21% vs 8% without chemotherapy; p=0.009) but not for chemoradiotherapy (five-year survival 10% vs 20% without chemoradiotherapy)5. Most recently, ESPAC 4, a multicenter, international, open-label randomised-controlled phase III trial compared six cycles of either adjuvant 1000 mg/m? gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m? oral capecitabine administered for 21 days followed by 7 days’ rest (one cycle) in 730 patients with resected PDAC, and reported an improvement in median survival from 25.5 months to 28 months (Hazard Ratio [HR] 0.82, 95% confidence interval [CI] 0.68-0.98) with combination chemotherapy6.Adjuvant chemotherapy, like all chemotherapy, is associated with morbidity and mortality7, and to date there is no way of identifying patients with resected PDAC, who are most likely to benefit from adjuvant treatment. In colorectal cancer, prognostic factors, including age, tumor differentiation, resection margin, T staging and presence of nodal disease, guide clinicians in identifying patients who have a higher risk of recurrence, and therefore may have a greater absolute benefit from adjuvant chemotherapy when weighed against the risks8. Nodal status is predictive of benefit from oxaliplatin-based chemotherapy in patients with node-positive resected colorectal cancer, and elderly patients (>70 years) do not derive additional benefit from oxaliplatin in combination with 5-fluorouracil-based chemotherapy9. Adjuvant chemotherapy following resection of PDAC improves OS6, but it is uncertain whether benefit is influenced by nodal and resection margin status, or other factors. The aim of this meta-analysis was thus to assess whether patients with nodal and resection margin negative PDAC derived similar benefit from adjuvant chemotherapy.METHODSIdentification of studiesRandomised phase II and III studies were identified using MEDLINE (host: Pubmed) and EMBASE (host: OvidSP) from beginning of records to present. The search strategy included the key words “pancrea*.ti,ab AND (tumour*.ti,ab OR cancer*.ti,ab OR neoplas*.ti,ab OR oncolog*.ti,ab OR maligna*.ti,ab OR carcin*.ti,ab OR metasta*.ti,ab OR tumor*.ti,ab); exp PANCREAS CANCER/; exp ADJUVANT CHEMORADIOTHERAPY/; exp ADJUVANT CHEMOTHERAPY/; exp ADJUVANT RADIOTHERAPY/. The results were limited to: Clinical Trials, Randomised Controlled Trials, Phase 2 Clinical Trials or Phase 3 Clinical Trials. Abstract presentations of the European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) were reviewed to identify relevant phase II and III studies not yet published. Eligibility criteriaRandomised-controlled phase II and III clinical trials, with at least one arm involving adjuvant chemotherapy for PDAC were considered. The trial population included patients with resectable PDAC suitable for surgery. Trials involving radiotherapy alone were excluded, to focus the analysis on the effects of adjuvant chemotherapy. Outcomes of interest were disease free survival (DFS), and 5-year OS.Data abstractionThe following data were collected from the original publication: name of study, authors’ names, year of publication, geographical region, titles of publication/presentation, phase of trial, control arm, intervention arm, dates trial opened and closed, number of patients in total, and in each arm, median and range of patients’ age, Eastern Cooperative Oncology Group performance status (ECOG PS), gender, location of tumor, proportion of patients with positive and negative resection margins, and proportion of patients with positive and negative lymph node status. In all patients, and separately for positive and negative resection margins and lymph node status, the following data were collected: median OS, 1 year OS, 2 year OS, 5 year OS, DFS, and p values, where available.Statistical analysisStudy characteristics were reported descriptively using means and proportions. Due to the presence of substantial inter-study clinical heterogeneity, studies reporting the HR for OS or DFS were weighted using the generic inverse variance method and pooled using random effects models10, irrespective of statistical heterogeneity. Among studies not reporting the HR for OS or DFS, a supplementary analysis exploring the odds of death at 2 and 5 years was performed. Data were weighted and pooled using the Mantel-Haenszel random-effect model. Statistical heterogeneity was assessed using the Cochran’s Q and I2 statistics. Subgroup analyses based on nodal and resection margin status were conducted as described by Deeks et al11. Sensitivity analyses were utilised to explore the influence of outlying data and related statistical heterogeneity. Meta-regression was performed to assess the influence of baseline variables on OS. Meta-regression comprised a univariable linear regression, weighted by individual study sample size, exploring the association between age, gender, ECOG PS, nodal and resection margin status and head versus body/tail of pancreas tumors on the log of the HR for OS, or the OR for survival at 5 years. Meta-regression was performed using SPSS version 21 (IBM Corp, Armonk, NY, USA) using the weighted least squares (mixed effect) function12. All statistical tests were two-sided, and statistical significance was defined as p<0.05. No corrections were made for multiple testing.RESULTSTen studies published between January 1993 and January 2017 comprising 3,644 patients were included in this meta-analysis. These included eight prospective phase III randomized-controlled trials, one prospective randomized phase II study and one prospective open-label non-randomized phase II study (sample size ranging from 61 to 1088). Amongst these, five included a control arm of surgery alone5,13,14,15,16, and five studies included a control arm of standard of care chemotherapy compared with an intervention arm of a different chemotherapy regimen6,17,18,19,20. The schematic of the methodology applied to identify studies for inclusion within this meta-analysis are illustrated in Supplementary Material Figure 1. The details of the included studies are illustrated in Table 1.The median age of patients included within the ten studies was 63 years (range 24-84), and 46% were male. Among the 2,268 patients where ECOG PS was reported, 42% were PS 0, and 51% PS 1. Tumor location was reported in 719 patients, and the majority of these (82%) had head of pancreas (HOP) tumors. There was data available regarding nodal status and resection margin status in 3,524 patients; 33% were node negative and 67% had margin negative (R0) resections. Effects of adjuvant therapy on DFS in patients with resected PDACThere were 4 studies15,16,18,20 which reported data from multivariable analyses for DFS. In these studies, there was a significant beneficial effect of adjuvant chemotherapy on DFS (HR 0.67, 95% CI 0.48-0.93, p=0.02) (Figure 1). A sensitivity analysis including studies15,16 where the control arm was surgery alone, reported a greater magnitude of effect of the experimental arm on DFS (HR 0.57, 95% CI 0.49-0.76, p<0.001).Effects of adjuvant therapy on OS in patients with resected PDAC There were 7 studies which reported data from multivariable analyses for OS5,6,15,16,17,18,20. In these studies, there was a significant beneficial effect of adjuvant chemotherapy on OS (HR 0.81, 95% CI 0.70-0.95, p=0.007, see Figure 2). One study of chemoradiotherapy5 (Neoptolemos et al 2004) was an outlier, with a non-significant association with worse OS. Exclusion of this study in a sensitivity analysis resulted in a numerically greater effect on OS (HR 0.77, 95% CI 0.68-0.87, p<0.001). A sensitivity analysis including studies where the control arm was surgery alone, found a greater magnitude of effect of the experimental arm on OS (HR 0.74, 95% CI 0.64-0.87, p=0.0001).Supporting analyses were performed for the odds of death at 2 years and at 5 years. The 2-year analysis comprised data from 8 studies5,13,14,15,16,17,18,20 and demonstrated a non-significant association with death (Odds ratio [OR] 0.85, 95% CI 0.68-1.06, p=0.16) (Figure 3). Once again, the chemoradiotherapy study5 was an outlier, with a significant association with worse odds of death. Exclusion of this study in a sensitivity analysis resulted in a significant reduction in the odds of death at 2 years (OR 0.80, 95% CI 0.68-0.95, p=0.009). The 5-year analysis comprised data from 9 studies5,6,13,14,15,16,17,18,20 and demonstrated a significant association with death (OR 0.60, 95% CI 0.43-0.85, p=0.004) (Figure 4). The chemoradiotherapy study5 was again an outlier, with a significant association with worse odds of death. Exclusion of this study in a sensitivity analysis resulted in a numerically greater effect on the odds of death at 5 years (OR 0.53, 95% CI 0.41-0.70, p<0.001).Impact of addition of adjuvant therapy on OS, depending on nodal status, in patients with resected PDACThree studies reported data based on nodal involvement15,16,20. There was a numerical, but non-significantly greater relative effect of adjuvant chemotherapy on OS in node negative patients (HR 0.58 compared with 0.71, p for difference = 0.29) (Figure 5).Impact of addition of adjuvant therapy on OS, depending on resection margin status, in patients with resected PDACThree studies reported data based on resection margin status15,16,20. There was no difference in effect of adjuvant treatment on OS in patients with R0 or R1 resection margins (HR 0.70 compared with 0.69, p for difference = 0.95) (Figure 6).Meta-regression analysis of factors predicting benefit from adjuvant chemotherapyMeta-regression analysis evaluated predictors of benefit from adjuvant chemotherapy, assessing the effect of variables on the HR for OS. Greater chemotherapy benefit was observed among studies with higher proportions of patients with ECOG PS of 0 (p=0.04). Other factors including age, gender, proportion of patients with R0 resection and proportion of patients with nodal involvement were not found to be significant, and anatomical location of tumor was unable to be assessed, as this data was included in only 2 studies (Table 2).Meta-regression analysis assessing the effect of variables on the OR for death at 5 years was also performed. This concluded that the most significant factor on OR for death at 5 years was the tumor being located in the head of the pancreas (p=0.04). Other factors, including age, gender, proportion of patients with R0 resection, proportion of patients with nodal involvement and PS were not found to be significant (Table 2). DISCUSSIONAdjuvant chemotherapy resulted in improved DFS and/or OS in patients with resected PDAC in a selection of studies with control groups comprising surgery or older chemotherapy regimens. In this meta-analysis of patients treated with adjuvant chemotherapy after resection of PDAC, nodal status and resection margin status were not found to have a significant impact on benefit from chemotherapy. The effects of nodal and resection margin status on OS in patients with resected PDAC receiving adjuvant therapy varies between individual studies included within this meta-analysis; the ESPAC 1 trial reported that negative resection margins and node negative disease were significantly associated with better OS21,22. The ESPAC 3 trial also reported that negative lymph node status was associated with improved OS on univariate survival analysis, as was negative resection margin status18. The ESPAC 2 study reported that nodal positivity and resection margin status were not significantly associated with response to treatment, in those who had chemotherapy and those who did not5. Kosuge et al14 reported that nodal involvement was associated with significantly worse OS on multivariable analysis. Oettle et al16 also reported that within the CONKO-001 trial, nodal status was a significant prognostic factor for DFS and OS, but resection margin status was not. Regine et al17 also reported that while nodal status was a significant factor in OS for patients with head of pancreas tumors, resection margin status was not. Secondary analysis of the Radiation Therapy Oncology Group 9704 (RTOG 9704) trial, evaluating significance of lymph node status on DFS and OS in patients with resected PDAC, reported that the number of total nodes examined, and number of positive nodes and lymph node ratio were all associated with OS and DFS; to have ≤15 nodes examined was significantly associated with worse OS; increased number of positive nodes was also associated with a worse OS, and increased lymph node ratio with worse OS23. In other studies not included within this meta-analysis (they did not fulfil eligibility criteria), the presence of lymph node metastases has been identified as a factor associated with poor outcome after adjuvant chemotherapy in patients with resected PDAC, independent of resection margin status24,25. A recent sub-study evaluating the impact of positive resection margins on OS and recurrence in the 1,151 patients enrolled in the ESPAC 3 trial, reported that R1 resection margins were associated with reduced recurrence-free survival and OS, and also that resection margin involvement was associated with increased risk of local recurrence26. Another study which investigated the impact of chemoradiotherapy in a multicenter study of 152 patients who underwent an R0 resection for PDAC reported a benefit of chemoradiotherapy only in patients with node positive disease (HR 0.68, 95% CI 0.33-0.88, p=0.014)27. A large study of 747 patients randomised to chemoradiotherapy following surgery, or surgery alone, reported that only patients with lymph node-positive disease appeared to benefit from chemoradiotherapy, regardless of resection margin status, and appeared to negatively impact survival in the lymph node negative population28. A recent study reported at ASCO this year, which was not included in this meta-analysis as was not within timeframe studied, describing the results of a phase III randomised clinical trial investigating adjuvant modified 5-Fluorouracil/irinotecan/oxaliplatin (FOLFIRINOX) versus gemcitabine in 493 patients with resected PDAC, reported an improvement in median DFS for the modified FOLFIRINOX arm (21.6 vs 12.8 months respectively). Node positive disease (HR 1.67, 1.25-2.22, p<0.001) and R1 resection status (HR 1.45, 1.16-1.81, p=0.001), were identified as poor prognostic markers for DFS29.As survival in patients with resected PDAC receiving adjuvant therapy is still poor, in addition to studies focusing on adjuvant therapy, the role of neoadjuvant therapy in PDAC requires further investigation. Neoadjuvant therapy in these patients has been reported to achieve local control of disease, and has been reported to convert approximately 40% of locally advanced pancreatic cancer to R0 resectability30. A recent meta-analysis reported that up to 43% of patients underwent surgical resection following FOLFIRINOX chemotherapy, and between 50-100% of these had an R0 resection31. There is an unmet need to identify patients most likely to benefit from neoadjuvant therapy. A retrospective neoadjuvant study of 236 elderly patients with PDAC (>70 years) reported no significant difference in survival between those who did, and those who did not receive neoadjuvant therapy32. The role of potential prognostic factors, in addition to lymph node status and resection margin status, such as tumor budding, also have exploratory value within PDAC. Tumor budding, which is the presence of de-differentiated single tumor cells or small cell clusters at the invasive front of gastrointestinal carcinomas, is well-recognised as an adverse prognostic factor in colorectal cancer, and has also been identified as an independent adverse prognostic factor in PDAC33. Another area of interest for the future is whether mismatch repair deficiency and microsatellite instability are associated with response to chemotherapy in PDAC, as in colorectal cancer; one study reported no survival advantage from pyrimidine analogue adjuvant chemotherapy in PDAC with mismatch-repair deficiency34. Further research in these areas is needed.A limitation in evaluating results from different studies regarding resection margin status is that the definitions of R0/R1 resections have changed over time35, and studies frequently do not report which definition they have used. Many centers in Europe and Australia use the minimum 1mm margin to define an R0 resection. However, some centers use the 0mm minimum margin definition, and reported rates of R0 resection in different trials, accordingly, can vary considerably35. The International Study Group of Pancreatic Surgery (ISGPS) has recommended a 1mm resection margin for R0 resection, with specific recommendations on seven different margins36. There is also discussion and increasing evidence to support a 2mm margin clearance, which may be associated with better OS37. These different definitions and lack of clarity within trials of which definition they have used, makes interpretation of meta-analyses in this area more difficult. In addition, studies often do not report which margins they analyze35. Within this meta-analysis, the trials span 23 years and it is extremely likely that different pathology techniques and definitions have evolved over this time. Assessment of lymph nodes pathologically is also evolving, changing the focus from number of positive nodes to lymph node ratio. Studies assessing the significance of number of nodes assessed, number of positive lymph nodes and lymph node ratio, have been carried out38-40. A large study of 811 patients who underwent pancreatoduodenectomy for PDAC between 2001 and 2012 assessed these factors, and reported that the number of positive lymph nodes, rather than number of nodes assessed, or lymph node ratio, was the most accurate prognostic factor for survival41. Another study of 119 patients undergoing pancreatectomy for PDAC, with regional lymph node dissection, also reported that the number of positive nodes, but not lymph node ratio was a more powerful prognostic factor39. Another limitation of the current manuscript is that this was a literature-based meta-analysis, with associated publication bias, with inference from study-level data in meta-regression, rather than individual patient data. Furthermore, only three studies included data regarding nodal status in this meta-analysis, and so definitive conclusions on the influence of nodal status on survival outcomes cannot be made. However, this study does include a large number of patients from prospective trials of adjuvant treatment following resection of PDAC, and provides relatively robust evidence to support adjuvant therapy in all patients with resected PDAC, irrespective of nodal or resection margin status.CONCLUSIONSAdjuvant chemotherapy is recommended for all patients with resected PDAC who are clinically fit enough. Positive predictive factors for survival were being ECOG PS 0 and having a head of pancreas tumor. This study concludes that the relative benefit of adjuvant chemotherapy seems similar for patients with both node positive and node negative disease, and who undergo R0 or R1 resections, and so this meta-analysis provides level 1 evidence supporting the use of adjuvant treatment in resected PDAC, irrespective of nodal or resection margin status, and will inform international guidelines. ACKNOWLEDGEMENTSNo acknowledgements.REFERENCESSEER, SEER Cancer Statistics Review 1975-2015: Cancer of the Pancreas (Invasive) (online). 2017; Accessed on 16/01/2018. Available at: . Accessed 11/4/17.Sener SF, Fremgen A, Menck HR et al. Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985-1995, using the National Cancer Database. J Am Coll Surg. 1999; 189:1-7.Sohn TA, Yeo CJ, Cameron JL et al. Resected adenocarcinoma of the pancreas – 616 patients: results, outcomes and prognostic indicators. J Gastrointest Surg. 2000; 4:567-479Kalser MH & Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985; 120: 899-903Neoptolemos JP, Stocken DD, Friess H et al. A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer. NEJM. 2004; 350: 1200-1210.Neoptolemos JP, Palmer DH, Ghaneh P et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncology. 2017; 389(10073): 1011-1024.Ghaneh P and Neoptolemos JP. Conclusions from the European Study Group for Pancreatic Cancer adjuvant trial of chemoradiotherapy and chemotherapy for pancreatic cancer. Surg Oncol N Am. 2004; 13(4): 567-87. vii-viii.Kim JH. Chemotherapy for colorectal cancer in the elderly. World J Gastroenterol. 2015; 21(17): 5158-5166.Tournigand C, André T, Bonnetain F et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol 2012; 30: 3353–3360.DerSimonian R and Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-188.Deeks JJ, Higgins JPT, Altman DG, et al. Analysing and presenting results. Cochrane Handbook for Systematic Reviews of Interventions 4 2 5 In: The Cochrane Library. Chichester. UK: John Wiley & Sons, Ltd; 2006:468-472.Stanley TD and Doucouliagos H. Neither fixed nor random: weighted least squares meta-regression. Res Synth Methods. 2017; 8(1):19-42.Bakkevold K, Arnesi? B, Dahl O et al. Adjuvant Combination Chemotherapy (AMF) Following Radical Resection of Carcinoma of the Pancreas and Papilla of Vater – Results of a Controlled, Prospective, Randomised Multicentre Study. Eur J Cancer. 1993; 29A(5), pp698-703.Kosuge T, Kiuchi T, Mukai K et al. A Multicenter Randomized Controlled Trial to Evaluate the Effect of Adjuvant Cisplatin and 5-Fluorouracil Therapy after Curative Resection on Cases of Pancreatic Cancer. Jpn J Clin Oncol. 2006; 36(3): 159-165.Ueno H, Kosuge T, Matsuyama Y et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. British Journal of Cancer, 2009; 101:908-915.Oettle H, Neuhaus P, Hochhaus A et al. Adjuvant Chemotherapy With Gemcitabine and Long-Term Outcomes Among Patients With Resected Pancreatic Cancer – The CONKO-001 Randomized Trial. JAMA. 2013; 310(14):1473-1481.Regine WF, Winter KA, Abrams RA et al. Fluorouracil vs Gemcitabine Chemotherapy Before and After Fluorouracil-Based Chemoradiation Following Resection of Pancreatic Adenocarcinoma. JAMA. 2008; 299(9):1019-1026.Neoptolemos JP, Stocken DD, Bassi C et al. Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial. JAMA. 2010; 304(10): 1073-1081.Fensterer H, Schade-Brittinger C, Müller HH et al. Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP). Annals of Oncology. 2013; 24: 2576-2581.Uesaka K, Boku N, Fukutomi A et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01); Lancet. 2016; 388:248-57.Neoptolemos JP, Stocken DD, Dunn JA et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001. 234(6):758-768.Neoptolemos JP, Dunn JA, Stocken DD et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001; 358:1576-1585.Showalter TN, Winter KA, Berger AC et al.. The influence of total nodes examined, number of positive nodes, and lymph node ratio on survival after surgical resection and adjuvant chemoradiation for pancreatic cancer: a secondary analysis of RTOG 9704. Int J Radiat Oncol Biol Phys. 2011; 81(5): 1328-1335.John BJ, Naik P, Ironside A et al. Redefining the R1 resection for pancreatic ductal adenocarcinoma: tumour lymph nodal burden and lymph node ratio are the only prognostic factors associated with survival. 2013. HPB (Oxford); 15(9): 674-680.Aoyoma T, Murakawa M, Katayama Y et al. Lymphatic invasion is an independent prognostic factor in pancreatic cancer patients undergoing curative resection followed by adjuvant chemotherapy with gemcitabine or S-1. Hepatogastroenterology. 2015; 62(138): 472-477.Ghaneh P, Kleef J, Halloran CM et al. The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma. Ann Surg, 2017; Oct 24 [Epub ahead of print]. Accessed on 12/02/2018. Available at: Z, Luo G, Guo M et al. Lymph node status predicts the benefit of adjuvant chemoradiotherapy for patients with resected pancreatic cancer. Pancreatology. 2015; 15(3): 253-258.Merchant NB, Rymer J, Koehler EAS et al. Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits?; J Am Coll Surg. 2009; 208(5):829-838.Conroy, Hammel P, Hebbar M et al. PRODIGE 24/CCTG PA.6, an Unicancer GI trial: a multicentre international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. 2018. Presented at ASCO General Meeting 4 June 2018, Chicago, USA. Polistina F, Di Natale G, Bonciarelli G et al. Neoadjuvant strategies for pancreatic cancer. World J Gastroenterol. 2014; 20(28):9374-9383.Suker M, Beumer BR; Sadot E et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncology. 2016; 17(6): 801-810.Cooper AB, Holmes HM, des Bordes JKA et al. Role of neoadjuvant therapy in the multimodality treatment of older patients with pancreatic cancer. J Am Coll Surg. 2014; 201(1):111-120.O’Connor K, Li-Chang HH, Kalloger SE et al. Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma. Am J Surg Pathol. 2015; 39(4):472-478.Riazy M, Kalloger SE, Sheffield BS et al. Mismatch repair status may predict response to adjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Mod Pathol. 2015; 28(10):1383-9.Chandrasegaram MD, Goldstein D, Simes J, et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br J Surg. 2015; 102:1459–1472.Bockhorn M, Uzunoglu FG, Adham M et al. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2014; 155: 977–988.Gebauer F, Tachezy M, Vashist YK et?al. Resection margin clearance in pancreatic cancer after implementation of the Leeds Pathology Protocol (LEEPP): clinically relevant or just academic? World J Surg. 2015; 39: 493–499.Yamada S, Fujii T, Kanda M et al. Lymph node ratio as parameter of regional lymph node involvement in pancreatic cancer. Langenbecks Arch Surg. 2016; 401(8):1143-1152.Murakami Y, Uemura K, Sudo T et al. Number of metastatic lymph nodes, but not lymph node ratio, is an independent prognostic factor after resection of pancreatic carcinoma. J Am Coll Surg. 2010; 211(2): 196-204. Mirkin KA, Hollenbeak CS and Wong J et al. Greater lymph node retrieval and lymph node ratio impacts survival in resected pancreatic cancer. J Surg Res. 2017; 220:12-24.Strobel O, Hinz U, Gluth A et al. Pancreatic adenocarcinoma: number of positive nodes allows to distinguish several N categories. Ann Surg. 2015; 261(5): 961-969.TABLES/FIGURESTable 1: Details on studies included in the meta-analysisTable 2: Predictors of benefit from adjuvant chemotherapy using meta-regression - variables affecting HR for OS and OR for death at 5 yearsFigure 1a: Forest plot of impact of adjuvant chemotherapy on disease free survival (DFS) in patients with resected PDACFigure 1b: Forest plot of impact of adjuvant chemotherapy on overall survival (OS) in patients with resected PDACFigure 1c: Forest plot of impact of adjuvant chemotherapy on 2-year survival in patients with resected PDACFigure 1d: Forest plot of impact of adjuvant chemotherapy on 5-year survival in patients with resected PDACFigure 2: Forest plot of impact of nodal status on overall survival (OS) in patients with resected PDAC who received adjuvant treatmentFigure 3: Forest plot of impact of resection status on overall survival (OS) in patients with resected PDAC who received adjuvant treatmentSupplementary Material Figure 1: Schematic of methodology to identify studies for inclusion within meta-analysisSupplementary Material Figure 2: The Cochrane Risk of Bias Assessment ToolTable 1: Details on studies included in the meta-analysisStudyTrial arms*Experimental armPatients (n) by armR0n (%)R1n (%)Node negativen (%)Node positiven (%)NorwayCSurgery alone3131 (100)019 (61)11 (35)Bakkevold et al 1993ESurgery and chemotherapy – 5-FU 500mg/m2, doxorubicin 40mg/m2, mitomycin C 6mg/m23030 (100)022 (73)8 (27)ESPAC 1CSurgery and no chemotherapy142119 (84)23 (16)51 (36)82 (58)Neoptolemos et al 2001, 2004ESurgery and chemotherapy - leucovorin 20mg/m2, 5-FU 425mg/m2147119 (81)28 (19)68 (46)73 (50)JSAPCSurgery alone4444 (100)035 (80)9 (20)Kosuge et al, 2006ESurgery and chemotherapy – cisplatin 80mg/m2, 5-FU 500mg/m24545 (100)023 (51)12 (27)CONKO-001CSurgery alone175148 (85)27 (15)48 (27)127 (73)Oettle et al, 2007, 2013ESurgery and chemotherapy – gemcitabine 1000mg/m2179145 (81)34 (19)52 (29)127 (71)RTOG 9704CSurgery and 5-FU 250mg/m2230102 (44)75 (33)82 (35)148 (65)Regine et al, 2008ESurgery and gemcitabine 1000mg/m222186 (39)77 (35)70 (32)151 (68)JSAP-02CSurgery alone6052 (87)8 (13)18 (30)42 (70)Ueno et al, 2009ESurgery and gemcitabine 1000mg/m25847 (81)11 (19)19 (33)39 (67)ESPAC 3CSurgery and 5-FU plus folinic acid 20mg/m2 5-Fu 425mg/m2486356 (65)195 (35)162 (30)387 (70)Neoptolemos et al, 2010ESurgery and 5-FU plus folinic acid, gemcitabine 1000mg/m2478348 (65)189 (35)145 (27)391 (73)ATIPCSurgery and gemcitabine 1000mg/m2179145 (81)34 (19)52 (29)127 (71)Fensterer et al, 2013ESurgery and gemcitabine 1000mg/m2, cetuximab 400mg/m2 (loading dose) then 250mg/m27659 (78)17 (22)21 (28)53 (72)JASPAC-01CSurgery and gemcitabine 1000mg/m2190164 (86)26 (14)73 (38)117 (62)Uesaka et al, 2016ESurgery and S-1 40/50/60mg per BSA187164 (88)23 (12)67 (36)120 (64)ESPAC 4CSurgery and gemcitabine 1000mg/m2366147 (40)219 (60)67 (18)299 (82)Neoptolemos et al, 2017ESurgery and gemcitabine 1000mg/m2 and capecitabine 1660mg/m2/day364143 (39)221 (61)76 (21)288 (79)5-FU = FluorouracilESPAC = European Study Group for Pancreatic CancerJSAP =Japanese Study Group of Pancreatic Therapy in Pancreatic CancerCONKO = Charité OnkologieATIP = Adjuvant Therapy In Pancreatic cancerRTOG = Radiation Therapy Oncology Group BSA = Body Surface Area*C = Control arm; E = Experimental arm; R0 = resection margin negative; R1 = resection margin positive.Table 2: Predictors of benefit from adjuvant chemotherapy using meta-regression - variables affecting HR for OS and OR for death at 5 yearsHR for OSHR for OSOR for death at 5 yearsOR for death at 5 yearsVariableβpβpMedian age-0.3410.45-0.2210.57Female gender0.1800.700.4940.18Proportion of patients with R0 resection-0.4770.28-0.4830.19Proportion of patients with nodal involvement0.5410.21-0.2160.58Performance status 0-0.998?0.04-0.815?0.39Proportion with head of pancreas tumoursNE?0.9560.04Proportion with body/tail of pancreas tumoursNE?-0.6830.32? Only 2 studies with data? Data available from only 4 studies. Figure 1:Figure 2:Figure 3:Supplementary Material Figure 1: Schematic of methodology to identify studies for inclusion within meta-analysisSupplementary Material Figure 2 – The Cochrane Risk of Bias Assessment Tool ................
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