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Background: Small intestinal adenocarcinomas (SIAs) are rare. Hence, randomized controlled trials are lacking and understanding of the disease features is limited. This nationwide cohort investigates incidence, treatment and prognosis of SIA patients, to improve disease outcome., Patients and Methods: Data of 2697 SIA patients diagnosed from January 1999 through December 2019 were retrieved from the Netherlands Cancer Registry and Pathology Archive. Incidence was calculated using the revised European Standardized Rate. The influence of patient and tumor characteristics on overall survival (OS) was studied using survival analyses., Results: The age-standardized incidence rate almost doubled from 0.58 to 1.06 per 100,000 person-years, exclusively caused by an increase in duodenal adenocarcinomas. OS did not improve over time. Independent factors for a better OS were a younger age, jejunal tumors, Lynch syndrome and systemic therapy. Only 13.8% of resected patients was treated with adjuvant chemotherapy, which improved OS compared to surgery alone in stage III disease (HR 0.47 (0.35-0.61)), but not in the limited group of deficient mismatch repair (MMR) patients (n = 53, HR 0.93 (0.25-3.47)). In the first-line setting, CAPOX was associated with improved OS compared to FOLFOX (HR 0.51 (0.36-0.72)). For oligometastatic patients, a metastasectomy significantly improved OS (HR 0.54 (0.36-0.80))., Conclusions: The incidence of SIAs almost doubled in the past 20 years, with no improvement in OS. This retrospective non-randomized study suggests the use of adjuvant chemotherapy for stage III disease and first-line CAPOX for metastatic patients. For selected oligometastatic patients, a metastasectomy may be considered. MMR-status testing could aid in clinical decision-making., Competing Interests: Declaration of Competing Interest The author declares the following financial interests/personal relationships which may be considered as potential competing interests: L.V. received consultancy fees from Bayer, MSD, Genentech, Servier, and Pierre Fabre, but these had no relation to the content of this publication. L.V. is currently an employee of Genentech Inc., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers., Methods: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test., Results: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501)., Conclusion: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice., (© The Author(s) 2023. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Surgical outcome after pancreatoduodenectomy for duodenal adenocarcinoma could differ from pancreatoduodenectomy for other cancers, but large multicenter series are lacking. This study aimed to determine surgical outcome in patients after pancreatoduodenectomy for duodenal adenocarcinoma, compared with other periampullary cancers, in a nationwide multicenter cohort., Methods: After pancreatoduodenectomy for cancer between 2014 and 2019, consecutive patients were included from the nationwide, mandatory Dutch Pancreatic Cancer Audit. Patients were stratified by diagnosis. Baseline, treatment characteristics, and postoperative outcome were compared between groups. The association between diagnosis and major complications (Clavien-Dindo grade III or higher) was assessed via multivariable regression analysis., Results: Overall, 3113 patients, after pancreatoduodenectomy for cancer, were included in this study: 264 (8.5%) patients with duodenal adenocarcinomas and 2849 (91.5%) with other cancers. After pancreatoduodenectomy for duodenal adenocarcinoma, patients had higher rates of major complications (42.8% vs. 28.6%; p < 0.001), postoperative pancreatic fistula (International Study Group of Pancreatic Surgery [ISGPS] grade B/C; 23.1% vs. 13.4%; p < 0.001), complication-related intensive care admission (14.3% vs. 10.3%; p = 0.046), re-interventions (39.8% vs. 26.6%; p < 0.001), in-hospital mortality (5.7% vs. 3.1%; p = 0.025), and longer hospital stay (15 days vs. 11 days; p < 0.001) compared with pancreatoduodenectomy for other cancers. In multivariable analysis, duodenal adenocarcinoma was independently associated with major complications (odds ratio 1.14, 95% confidence interval 1.03-1.27; p = 0.011)., Conclusion: Pancreatoduodenectomy for duodenal adenocarcinoma is associated with higher rates of major complications, pancreatic fistula, re-interventions, and in-hospital mortality compared with patients undergoing pancreatoduodenectomy for other cancers. These findings should be considered in patient counseling and postoperative management., (© 2022. The Author(s).)

Background: Periampullary adenocarcinoma consists of pancreatic adenocarcinoma (PDAC), distal cholangiocarcinoma (DC), ampullary cancer (AC), and duodenal adenocarcinoma (DA). The aim of this study was to assess treatment modalities and overall survival by tumor origin., Methods: Patients diagnosed with non-metastatic periampullary cancer in 2012-2018 were identified from the Netherlands Cancer Registry. OS was studied with Kaplan-Meier analysis and multivariable Cox regression analyses, stratified by origin., Results: Among the 8758 patients included, 68% had PDAC, 13% DC, 12% AC, and 7% DA. Resection was performed in 35% of PDAC, 56% of DC, 70% of AC, and 59% of DA. Neoadjuvant and/or adjuvant therapy was administered in 22% of PDAC, 7% of DC, 7% of AC, and 12% of DA. Three-year OS was highest for AC (37%) and DA (34%), followed by DC (21%) and PDAC (11%). Adjuvant therapy was associated with improved OS among PDAC (HR = 0.62; 95% CI 0.55-0.69) and DC (HR = 0.69; 95% CI 0.48-0.98), but not AC (HR = 0.87; 95% CI 0.62-1.22) and DA (HR = 0.85; 95% CI 0.48-1.50)., Conclusion: This retrospective study identified considerable differences in treatment modalities and OS between the four periampullary cancer origins in daily clinical practice. An improved OS after adjuvant chemotherapy could not be demonstrated in patients with AC and DA., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers., Methods: Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015-2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed., Results: Median ADAM12 levels were 161 (IQR 79-352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P = 0.04), but not after adjustment. In distal cholangiocarcinoma (n = 33), high ADAM12 levels predicted poor OS in univariable analysis (P = 0.02), but not in PDAC (P = 0.63). PDAC patients (n = 135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P = 0.02), whereas those with low levels did not (21 vs 21 months, P = 0.87)., Conclusion: High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC., Methods: From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated., Results: A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 < 274 were independent factors predicting a better OS (c-index: 0.61). WHO ps >1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79)., Conclusions: Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients., (© 2021 Wiley Periodicals LLC.)

Importance: To date, no randomized clinical trials have investigated perioperative systemic therapy relative to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM)., Objective: To assess the feasibility and safety of perioperative systemic therapy in patients with resectable CPM and the response of CPM to neoadjuvant treatment., Design, Setting, and Participants: An open-label, parallel-group phase 2 randomized clinical trial in all 9 Dutch tertiary centers for the surgical treatment of CPM enrolled participants between June 15, 2017, and January 9, 2019. Participants were patients with pathologically proven isolated resectable CPM who did not receive systemic therapy within 6 months before enrollment., Interventions: Randomization to perioperative systemic therapy or CRS-HIPEC alone. Perioperative systemic therapy comprised either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin. Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles., Main Outcomes and Measures: Proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity. Key secondary outcomes were centrally assessed rates of objective radiologic and major pathologic response of CPM to neoadjuvant treatment. Analyses were done modified intention-to-treat in patients starting neoadjuvant treatment (experimental arm) or undergoing upfront surgery (control arm)., Results: In 79 patients included in the analysis (43 [54%] men; mean [SD] age, 62 [10] years), experimental (n = 37) and control (n = 42) arms did not differ significantly regarding the proportions of macroscopic complete CRS-HIPEC (33 of 37 [89%] vs 36 of 42 [86%] patients; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74) and Clavien-Dindo grade 3 or higher postoperative morbidity (8 of 37 [22%] vs 14 of 42 [33%] patients; risk ratio, 0.65; 95% CI, 0.31-1.37; P = .25). No treatment-related deaths occurred. Objective radiologic and major pathologic response rates of CPM to neoadjuvant treatment were 28% (9 of 32 evaluable patients) and 38% (13 of 34 evaluable patients), respectively., Conclusions and Relevance: In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM, justifying a phase 3 trial., Trial Registration: ClinicalTrials.gov Identifier: NCT02758951.

Introduction: The peritoneum is a predilection site for gastric cancer metastases. Current standard treatment for gastric cancer patients with synchronous peritoneal metastases is palliative systemic therapy. However, its efficacy is largely unknown. The aim of this study was to investigate the incidence, treatment and survival patterns of gastric cancer patients with synchronous peritoneal metastases in the Netherlands., Methods: All newly diagnosed gastric adenocarcinoma patients with synchronous peritoneal metastases between 1999 and 2017 were selected from the Netherlands Cancer Registry (NCR). Incidence, treatment and survival patterns were analyzed., Results: In total, 3,773 patients were identified from the NCR. The incidence of synchronous peritoneal metastases in gastric cancer patients increased from 18% in 2008 to 27% in 2017. The use of systemic therapy increased from 15% in 1999-2002 to 43% in 2013-2017 (p < 0.001). The median survival of the entire cohort did not significantly increase over time. Median survival of patients treated with systemic therapy increased from 7.4 months in 1999-2002 to 9.4 months in 2013-2017 (p = 0.005). In contrast, median survival of patients not treated with systemic therapy decreased from 3.3 months in 1999-2002 to 2.1 months in 2013-2017 (p < 0.001). Some clinical and pathological data such as the extent of the peritoneal metastases were not available., Conclusion: Synchronous peritoneal metastases are increasingly diagnosed in gastric cancer patients. In recent years, more patients were treated with systemic treatment and survival of these patients increased. However, as survival of the entire group did not improve over time, the effect of systemic therapy remains unknown.

Introduction: Ampullary cancer is rare and as a result epidemiological data are scarce. The aim of this population-based study was to determine the trends in incidence, treatment and overall survival (OS) in patients with ampullary adenocarcinoma in the Netherlands between 1989 and 2016., Methods: Patients diagnosed with ampullary adenocarcinoma were identified from the Netherlands Cancer Registry. Incidence rates were age-adjusted to the European standard population. Trends in treatment and OS were studied over (7 years) period of diagnosis, using Kaplan-Meier and Cox regression analyses for OS and stratified by the presence of metastatic disease., Results: In total, 3840 patients with ampullary adenocarcinoma were diagnosed of whom, 55.0% were male and 87.1% had non-metastatic disease. The incidence increased from 0.59 per 100,000 in 1989-1995 to 0.68 per 100,000in 2010-2016. In non-metastatic disease, the resection rate increased from 49.5% in 1989-1995 to 63.9% in 2010-2016 (p < 0.001). The rate of adjuvant therapy increased from 3.1% to 7.9%. In non-metastatic disease, five-year OS (95% CI) increased from 19.8% (16.9-22.8) in 1989-1995 to 29.1% (26.0-31.2) in 2010-2016 (logrank p < 0.001). In patients with metastatic disease, median OS did not significantly improve (from 4.4 months (3.6-5.0) to 5.9 months (4.7-7.1); logrank p = 0.06). Cancer treatment was an independent prognostic factor for OS among all patients., Conclusion: Both incidence and OS of ampullary cancer increased from 1989 to 2016 which is most likely related to the observed increased resection rates and use of adjuvant therapy., Competing Interests: Declaration of competing interest Drs. de Vos-Geelen reports grants, personal fees and non-financial support from Servier, personal fees from AstraZeneca, personal fees from MSD, personal fees from Pierre Fabre, personal fees from Amgen, outside the submitted work. Dr. ir. Geurts reports grants from Roche, grants from Pfizer, grants from Novartis, grants from Eisai, grants from Lilly, outside the submitted work. Dr. Haj Mohammad reports non-financial support from Servier, non-financial support from MSD, non-financial support from BMS, non-financial support from Eli Lily, non-financial support from Astra Zeneca, outside the submitted work. Dr. van Laarhoven reports grants and non-financial support from BMS, grants and non-financial support from Celgene, grants and non-financial support from Lilly, grants and non-financial support from Nordic, grants and non-financial support from Servier, grants from Bayer, grants from Merck Serono, grants from MSD, grants from Philips, outside the submitted work. Dr. Tjan-Heijnen reports grants and personal fees from Roche, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Lilly, personal fees from Accord Healthcare, grants from AstraZeneca, grants from Eisai, grants from Daiichi Sankyo, outside the submitted work. Dr. Valkenburg-van Iersel reports non-financial support from Servier, non-financial support from Pierre Fabre, non-financial support from Roche, outside the submitted work. Dr. Wilmink reports grants and non-financial support from Servier, non-financial support from MSD, non-financial support from AstraZeneca, grants and non-financial support from Celgene, grants from Halozyme, grants from Merck, grants from Roche, grants from Pfizer, grants from Amgen, grants from Novartis, outside the submitted work. The other authors have declared no conflicts of interests., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC., Materials and Methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy., Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34)., Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A relationship between quality of life (QoL) and survival has been shown for several types of cancer, mostly in clinical trials with highly selected patient groups. The relationship between QoL and survival for patients with pancreatic or periampullary cancer is unclear., Methods: This study analyzed QoL data from a prospective multicenter patient-reported outcome registry in patients with pancreatic or periampullary carcinoma registered in the nationwide Netherlands Cancer Registry (2015-2018). Baseline and delta QoL, between baseline and 3-month follow-up, were assessed with the Happiness, EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30), and QLQ-PAN26 questionnaires. The relationship between QoL and survival was assessed using Cox regression models, and additional prognostic value of separate items was assessed using Nagelkerke R2 (explained variance)., Results: For the baseline and delta analyses, 233 and 148 patients were available, respectively. Most were diagnosed with pancreatic adenocarcinoma (n=194; 83.3%) and had stage III disease (n=77; 33.0%), with a median overall survival of 13.6 months. Multivariate analysis using baseline scores indicated several scales to be of prognostic value for the total cohort (ie, happiness today, role functioning, diarrhea, pancreatic pain, and body image; hazard ratios all P<.05) and for patients without resection (ie, overall satisfaction with life, physical and cognitive functioning, QLQ-C30 summary score, fatigue, pain, constipation, diarrhea, and body image; hazard ratios all P<.05). Except for diarrhea, all QoL items accounted for >5% of the additional explained variance and were of added prognostic value. Multivariate analysis using delta QoL revealed that only constipation was of prognostic value for the total cohort, whereas no association with survival was found for subgroups with or without resection., Conclusions: In a multicenter cohort of patients with pancreatic or periampullary carcinoma, QoL scores predicted survival regardless of patient, tumor, and treatment characteristics. QoL scores may thus be used for shared decision-making regarding disease management and treatment choice.

Background: The value of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneally metastasized goblet-cell carcinoids (GCCs) and mixed adenoneuroendocrine carcinomas (MANECs) is currently unclear. We compared outcomes of CRS-HIPEC to surgery alone for peritoneally metastasized GCCs and MANECs., Patients and Methods: Two cohorts were obtained from the Netherlands Cancer Registry (n = 569): patients with peritoneally metastasized GCCs and MANECs treated with CRS-HIPEC in Dutch and Belgian centers (n = 45), and patients treated with surgery alone. Primary outcome was overall survival (OS). Secondary outcomes were morbidity and hospital mortality. After propensity score matching, OS was compared in univariate and multivariate analyses. A systematic literature review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from database inception to June 25, 2018., Results: After matching for sex, tumor stage, lymph node stage, and liver metastases, CRS-HIPEC was associated with improved median OS in the combined GCC and MANEC group and the separate GCC subgroup in univariate (GCC + MANEC: 39 vs. 12 months, P < .001; GCC: 39 vs. 12 months, P = .017) and multivariate analysis (GCC + MANEC: hazard ratio 4.27, 95% confidence interval 1.88-9.66, P = .001; GCC: hazard ratio 2.77, 95% confidence interval 1.06-7.26, P = .038). Acceptable grade III-IV morbidity (17.5%) and mortality (0) were seen after CRS-HIPEC. The literature review supported these findings., Conclusion: CRS-HIPEC is associated with substantial survival benefit in patients with peritoneally metastasized GCCs and MANECs compared to surgery alone and is a safe treatment option. These data support centralized care of GCC and MANEC patients with peritoneal spread in expert centers offering CRS-HIPEC., (Copyright © 2020. Published by Elsevier Inc.)

Background: The aim of this population-based study was to determine the prognostic value of the histologic subtypes mucinous (MAC), non-mucinous (AC) and signet ring cell (SRCC) adenocarcinoma among patients with appendiceal cancer., Methods and Materials: Data from the Netherlands Cancer Registry (NCR) of patients with primary appendiceal adenocarcinomas with MAC, AC and SRCC histologic subtype, diagnosed between 2001 and 2015 were used (n = 675). To categorize patients according to the recent histopathological classification, the NCR was linked with the Dutch Pathology Registry (PALGA). Log-rank tests and Kaplan-Meier analyses were performed to estimate overall survival (OS), and the cox proportional hazards model was run to identify prognostic factors., Results: AC was the most frequently encountered histologic subtype (50.9%), followed by MAC (35.8%) and SRCC (13.3%). In locoregional disease, histologic subtype was not a prognostic factor for OS with 5-year survival rates for patients with AC, MAC and SRCC of 60.0%, 60.5% and 69.6% respectively (p = 0.68). Metastatic disease was more common in SRCC (53.8%) than in MAC (38.8%) and AC (23.4%) (p < 0.0001). Median OS for patients with metastatic disease was 12.6, 27.7 and 18.2 months in AC, MAC and SRCC respectively (p < 0.005). MAC was associated with higher survival compared to AC (HR 0.48, 95%CI 0.34-0.69). In subanalyses, MAC was only a positive prognostic factor compared to AC in patients with peritoneal metastases (HR 0.42, 95%CI 0.28-0.62)., Conclusion: Histologic subtype had no prognostic relevance in locoregional or systemic metastatic disease in appendiceal adenocarcinoma. In peritoneal metastases, mucinous histologic subtype was a favorable prognostic factor, compared to non-mucinous and signet ring cell subtype., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce., Objective: The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA., Patients and Methods: Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated., Results: In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59)., Conclusions: Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Background: Nearly a quarter of patients with locally advanced (T4 stage) or perforated colon cancer are at risk of developing peritoneal metastases, often without curative treatment options. We aimed to determine the efficacy of adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with locally advanced colon cancer., Methods: This multicentre, open-label trial was done in nine hospitals that specialised in HIPEC in the Netherlands. Patients with clinical or pathological T4N0-2M0-stage tumours or perforated colon cancer were randomly assigned (1:1), with a web-based randomisation application, before resection of the primary tumour, to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy (experimental group) or to adjuvant systemic chemotherapy alone (control group). Patients were stratified by tumour characteristic (T4 or perforation), age (<65 years or ≥65 years), and surgical approach of the primary tumour resection (laparoscopic or open). Key eligibility criteria included age between 18 and 75 years, adequate clinical condition for HIPEC, and intention to start adjuvant systemic chemotherapy. Patients with metastatic disease were ineligible. Adjuvant HIPEC consisted of fluorouracil (400 mg/m 2 ) and leucovorin (20 mg/m 2 ) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m 2 ) for 30 min at 42°C, delivered simultaneously or within 5-8 weeks after primary tumour resection. In all patients without evidence of recurrent disease at 18 months, a diagnostic laparoscopy was done. The primary endpoint was peritoneal metastasis free-survival at 18 months, measured in the intention-to-treat population, with the Kaplan-Meier method. Adverse events were assessed in all patients who received assigned treatment. This study is registered with ClinicalTrials.gov, number NCT02231086., Findings: Between April 1, 2015, and Feb 20, 2017, 204 patients were randomly assigned to treatment (102 in each group). In the HIPEC group, two patients withdrew consent after randomisation. In this group, 19 (19%) of 100 patients were diagnosed with peritoneal metastases: nine (47%) during surgical exploration preceding intentional adjuvant HIPEC, eight (42%) during routine follow-up, and two (11%) during diagnostic laparoscopy at 18-months. In the control group, 23 (23%) of 102 patients were diagnosed with peritoneal metastases, of whom seven (30%) were diagnosed by laparoscopy at 18-months and 16 during regular follow-up (therefore making them ineligible for diagnostic laparoscopy). In the intention-to-treat analysis (n=202), there was no difference in peritoneal-free survival at 18-months (80·9% [95% CI 73·3-88·5] for the experimental group vs 76·2% [68·0-84·4] for the control group, log-rank one-sided p=0·28). 12 (14%) of 87 patients who received adjuvant HIPEC developed postoperative complications and one (1%) encapsulating peritoneal sclerosis., Interpretation: In patients with T4 or perforated colon cancer, treatment with adjuvant HIPEC with oxaliplatin did not improve peritoneal metastasis-free survival at 18 months. Routine use of adjuvant HIPEC is not advocated on the basis of this trial., Funding: Organization for Health Research and Development and the Dutch Cancer Society., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Small bowel adenocarcinoma (SBA) is rare despite the fact that the small bowel represents the longest part and has the largest surface of all alimentary tract sections. Its incidence is 50-fold lower than that of colorectal carcinoma. It is often diagnosed at an advanced stage due to atypical and late symptoms, its low index of suspicion, difficult endoscopic access and poor detection by radiological imaging, resulting in impaired outcome. Due to its rarity and being molecularly a unique intestinal cancer, data regarding its optimal management are relatively sparse., Material and Methods: A PubMed search was performed to identify relevant manuscripts that were recently published. Emerging data regarding the pathogenesis, the diagnosis and the treatment of SBA that resulted from recent research are discussed in this comprehensive review., Results: Genomic analysis has demonstrated that SBA is a molecularly unique intestinal cancer. Double balloon enteroscopy and capsule endoscopy are novel techniques which may result in earlier diagnosis and consequently in improvement of the generally poor prognosis. For clinically localized disease, the quality of surgery has recently been defined, with removal of at least 8-10 lymph nodes correlating with improved prognosis. Moreover, adjuvant chemotherapy seems to improve outcome of stage III disease. The combination of a fluoropyrimidine and oxaliplatin appears to be the most effective systemic chemotherapy for disseminated disease. Genomic profiling can identify potentially targetable genomic alterations in a significant proportion of SBA patients. The role of administration of targeted agents or immune checkpoint inhibitors is still unknown and subject of ongoing clinical trials. In the common case of peritoneal metastases, recent studies have shown that cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy may be an attractive treatment option in selected patients., Conclusions: SBA is a rare and unique malignancy, whose diagnostic approach and treatment are evolving, resulting in improved outcome.

Background: The multi-institutional registry in this study evaluated the outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases (PM) from small bowel adenocarcinoma (SBA)., Methods: A multi-institutional data registry including 152 patients with PM from SBA was established. The primary end point was overall survival (OS) after CRS plus HIPEC., Results: Between 1989 and 2016, 152 patients from 21 institutions received a treatment of CRS plus HIPEC. The median follow-up period was 20 months (range 1-100 months). Of the 152 patients, 70 (46.1%) were women with a median age of 54 years. The median peritoneal cancer index (PCI) was 10 (mean 12; range 1-33). Completeness of cytoreduction (CCR) 0 or 1 was achieved for 134 patients (88.2%). After CRS and HIPEC, the median OS was 32 months (range 1-100 months), with survival rates of 83.2% at 1 year, 46.4% at 3 years, and 30.8% at 5 years. The median disease-free survival after CCR 0/1 was 14 months (range 1-100 months). The treatment-related mortality rate was 2%, and 29 patients (19.1%) experienced grades 3 or 4 operative complications. The period between detection of PM and CRS plus HIPEC was 6 months or less (P = 0.008), and multivariate analysis identified absence of lymph node metastasis (P = 0.037), well-differentiated tumor (P = 0.028), and PCI of 15 or lower (P = 0.003) as independently associated with improved OS., Conclusion: The combined treatment strategy of CRS plus HIPEC achieved prolonged survival for selected patients who had PM from SBA with acceptable morbidity and mortality.

Background: The aim of this population-based study was to provide insight into the incidence, risk factors and treatment-related survival of patients with peritoneal metastases (PM) of small bowel adenocarcinoma (SBA)., Methods: Data from the Netherlands Cancer Registry were used. All patients diagnosed with SBA between 2005 and 2014 were included. The influence of patient and tumour characteristics on the odds of developing PM was analysed. Subsequently, for all further analyses, patients without synchronous PM of SBA were excluded. The log-rank test and Kaplan-Meier analyses were conducted to estimate survival, and the Cox proportional hazards model was used to evaluate the risk of death., Results: Of the 1428 included patients diagnosed with SBA, 181 (13%) presented with synchronous PM. Synchronous PM was found in 9% of the duodenal tumours and in 17% of the more distal tumours. Median overall survival of all patients with PM was 5.9 months, whereas survival of both 11 months was observed in patients treated with primary tumour resection or palliative chemotherapy and 32 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). Poor prognostic factors for survival were age ≥70 years (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.1-2.2), systemic metastases other than PM (HR 2.0, 95% CI 1.4-2.9) and an advanced (HR 1.9, 95% CI 1.3-3.0) or unknown T-stage (HR 2.1, 95% CI 1.2-3.5)., Conclusions: Synchronous PM was frequently encountered in SBA. Without treatment, prognosis was extremely poor. Survival was higher after primary tumour resection, palliative chemotherapy and CRS+HIPEC, but selection bias probably played a significant role calling for further clinical research., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background/purpose: Peritoneal metastases (PM) affect approximately one third of patients with metastatic small bowel adenocarcinoma (SBA). Treatment options are (1) systemic therapy ± palliative surgery and (2) cytoreductive surgery with intraperitoneal chemotherapy (CRS + IPC). Due to scarce evidence, PM from SBA represents a therapeutic challenge. This narrative review summarised and discussed the evidence that investigated available treatment options., Methods: Studies were discussed if they investigated first line systemic therapy for advanced SBA or CRS + IPC for PM from SBA. Extracted outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and grade III-V toxicity/morbidity., Results: Eighteen studies (15 observational, 3 phase II) that investigated systemic therapy and six observational studies that investigated CRS + IPC were reviewed. In studies that investigated systemic therapy, ORR, DCR, median PFS, median OS, and grade III-V toxicity ranged from 6% to 50%, 50% to 90%, 3 to 11 months, 8 to 20 months, and 10% to 68%, respectively. Fluoropyrimidine-oxaliplatin revealed favourable survival outcomes compared to fluoropyrimidine-irinotecan, fluoropyrimidine-cisplatin, fluoropyrimidine monotherapy, and other regimens. In studies that investigated CRS + IPC, median DFS, median OS, and grade III-V morbidity ranged from 10 to 12 months, 16 to 47 months, and 12% to 35%, respectively., Conclusion: Based on available evidence, fluoropyrimidine-oxaliplatin should be regarded as optimal first line systemic treatment. In selected patients, CRS + IPC appears safe and may be more effective than systemic therapy as single treatment. Future studies should evaluate survival and morbidity of CRS + IPC in larger cohorts, as well as the value of chemotherapy with targeted agents in metastatic SBA with subgroup analysis for PM from SBA.

Background: We conducted a population-based study to establish the incidence, treatment and overall survival over time of patients with small bowel adenocarcinoma., Material and Methods: All patients diagnosed with small bowel adenocarcinoma in the Netherlands between 1999 and 2013 were included (n = 1775). Age-standardized incidence rates were calculated per 100 000 person-years using the European standardized population rate. The influence of patient and tumor characteristics on the administration of chemotherapy was analyzed by means of a multivariable logistic regression analysis. The Cochran-Armitage trend test was conducted to evaluate trends in treatment and survival and the Cox proportional hazards model was used to identify prognostic factors of overall survival., Results: The incidence of small bowel adenocarcinomas increased, mainly due to an almost twofold increase of duodenal adenocarcinomas. Patients with locoregional duodenal tumors were less likely to undergo surgery (58%), towards 95% of the locoregional jejunal and ileal tumors (p < 0.0001). The use of chemotherapy doubled for adjuvant (7-15%) and palliative chemotherapy (19-37%). Median overall survival of patients with locoregional disease increased from 19 to 34 months (p = 0.0006), whereas median overall survival of patients with metastatic disease remained 4-5 months. Favorable prognostic factors for prolonged survival in locoregional disease, identified by multivariable survival analysis, included age <60 years, tumor stage I or II, diagnosis in 2009-2013, surgical treatment and chemotherapy. Favorable prognostic factors for prolonged survival in metastatic disease were age <50 years, jejunal tumors, surgical treatment and chemotherapy., Conclusion: Small bowel adenocarcinomas are rare tumors with an increasing incidence. The administration of adjuvant and palliative chemotherapy doubled, but median overall survival only increased for patients with locoregional disease. Given the rarity and dismal prognosis, it is important to develop international studies to determine the optimal treatment for these patients.

Background: Most patients with colorectal cancer (CRC) presenting with peritoneal carcinomatosis (PC) rely on palliative systemic treatment options. However, data on the use and effect of systemic treatment strategies, including targeted agents for the palliative treatment of colorectal PC, are lacking. We conducted a nationwide population-based study with data from the period in which the targeted agent bevacizumab was introduced in the Netherlands., Patients and Methods: The present study included all patients diagnosed from 2007 to 2014 with synchronous PC from CRC treated with only palliative systemic therapy. We assessed the use of bevacizumab, the standard choice of targeted treatment, in addition to first-line chemotherapy. Multivariable logistic regression analyses were performed to calculate the predictors for the additional prescription of bevacizumab. Survival estimates were calculated, and multivariable Cox analyses were performed to estimate the hazard ratios (HRs) of death stratified by the treatment received., Results: A total of 1235 patients received palliative chemotherapy, of whom 436 also received bevacizumab (35%). Patients aged ≥ 75 years and patients with PC from colonic tumors were less likely to receive chemotherapy plus bevacizumab. The addition of bevacizumab to palliative chemotherapy was associated with an improved overall median survival of 7.5 versus 11 months in both patients with isolated PC and those with concomitant extraperitoneal metastases. The improvement remained after adjustment for patient and tumor characteristics (HR, 0.7; 95% confidence interval, 0.64-0.83)., Conclusion: The results of the present nationwide population-based study support the rationale for bevacizumab in addition to palliative chemotherapy for patients with PC of CRC and underline the need for ongoing efforts to precisely determine the role of targeted therapy in the treatment of PC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Pancreatic cancer is the fourth largest cause of cancer death in the United States and Europe with over 100,000 deaths per year in Europe alone. The overall 5-year survival ranges from 2-7 % and has hardly improved over the last two decades. Approximately 15 % of all patients have resectable disease at diagnosis, and of those, only a subgroup has a resectable tumour at surgical exploration. Data from cohort studies have suggested that outcome can be improved by preoperative radiochemotherapy, but data from well-designed randomized studies are lacking. Our PREOPANC phase III trial aims to test the hypothesis that median overall survival of patients with resectable or borderline resectable pancreatic cancer can be improved with preoperative radiochemotherapy., Methods/design: The PREOPANC trial is a randomized, controlled, multicentric superiority trial, initiated by the Dutch Pancreatic Cancer Group. Patients with (borderline) resectable pancreatic cancer are randomized to A: direct explorative laparotomy or B: after negative diagnostic laparoscopy, preoperative radiochemotherapy, followed by explorative laparotomy. A hypofractionated radiation scheme of 15 fractions of 2.4 gray (Gy) is combined with a course of gemcitabine, 1,000 mg/m(2)/dose on days 1, 8 and 15, preceded and followed by a modified course of gemcitabine. The target volumes of radiation are delineated on a 4D CT scan, where at least 95 % of the prescribed dose of 36 Gy in 15 fractions should cover 98 % of the planning target volume. Standard adjuvant chemotherapy is administered in both treatment arms after resection (six cycles in arm A and four in arm B). In total, 244 patients will be randomized in 17 hospitals in the Netherlands. The primary endpoint is overall survival by intention to treat. Secondary endpoints are (R0) resection rate, disease-free survival, time to locoregional recurrence or distant metastases and perioperative complications. Secondary endpoints for the experimental arm are toxicity and radiologic and pathologic response., Discussion: The PREOPANC trial is designed to investigate whether preoperative radiochemotherapy improves overall survival by means of increased (R0) resection rates in patients with resectable or borderline resectable pancreatic cancer., Trial Registration: Trial open for accrual: 3 April 2013 The Netherlands National Trial Register - NTR3709 (8 November 2012) EU Clinical Trials Register - 2012-003181-40 (11 December 2012).

Background: Large multicenter series on outcomes and predictors of survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC) are scarce., Methods: Adults who underwent DP for PDAC in 17 Dutch pancreatic centers between January 2005 and September 2013 were analyzed retrospectively. The primary outcome was survival, and predictors of survival were identified using Cox regression analysis., Results: In total, 761 consecutive patients after DP were assessed, of whom 620 patients were excluded because of non-PDAC histopathology (n = 616) or a lack of data (n = 4), leaving a total of 141 patients included in the study [45 % (n = 63) male, mean age 64 years (SD = 10)]. Multivisceral resection was performed in 43 patients (30 %) and laparoscopic resection was performed in 7 patients (5 %). A major complication (Clavien-Dindo score of III or higher) occurred in 46 patients (33 %). Mean tumor size was 44 mm (SD 23), and histopathological examination showed 70 R0 resections (50 %), while 30-day and 90-day mortality was 3 and 6 %, respectively. Overall, 63 patients (45 %) received adjuvant chemotherapy. Median survival was 17 months [interquartile range (IQR) 13-21], with a median follow-up of 17 months (IQR 8-29). Cumulative survival at 1, 3 and 5 years was 64, 29, and 22 %, respectively. Independent predictors of worse postoperative survival were R1/R2 resection [hazard ratio (HR) 1.6, 95 % confidence interval (CI) 1.1-2.4], pT3/pT4 stage (HR 1.9, 95 % CI 1.3-2.9), a major complication (HR 1.7, 95 % CI 1.1-2.5), and not receiving adjuvant chemotherapy (HR 1.5, 95 % CI 1.0-2.3)., Conclusion: Survival after DP for PDAC is poor and is related to resection margin, tumor stage, surgical complications, and adjuvant chemotherapy. Further studies should assess to what extent prevention of surgical complications and more extensive use of adjuvant chemotherapy can improve survival.

Background: At a national level, it is unknown to what degree elderly patients with pancreatic or periampullary carcinoma benefit from surgical treatment compared to their younger counterparts. We investigated resection rates and outcomes after surgical treatment among elderly patients., Methods: From the Netherlands Cancer Registry, 20 005 patients diagnosed with primary pancreatic or periampullary cancer in 2005-2013 were selected. The associations between age (<70, 70-74, 75-79, ≥80 years) and resection rates were investigated using χ(2) tests, and surgical outcomes (30-, 90-day mortality) were evaluated using logistic regression analysis. Overall survival after resection was investigated by means of Kaplan-Meier and Cox proportional hazard regression analysis., Results: During the study period, resection rates increased in all age groups (<70 years: 20-30%, p < 0.001; ≥80 years: 2-8%, p < 0.001). Of 3845 patients who underwent tumour resection for pancreatic or periampullary carcinoma, the proportion of octogenarians increased from 3.5% to 5.5% (p = 0.03), whereas postoperative mortality did not increase (30-day: 6-3%, p = 0.06; 90-day: 9-8%, p = 0.21). With rising age, 30-day postoperative mortality increased (4-5-7-8%, respectively, p < 0.001), while 90-day mortality was 6-10-13-12% (p < 0.001) and three-year overall survival rates after surgery were 35-33-28-31%, respectively (p < 0.001). After adjustment for confounding factors, octogenarians who survived 90 days postoperative exhibited an overall survival close to younger patients [hazard ratio (≥80 vs. <70 years) = 1.21, 95% confidence interval (0.99-1.47), p = 0.07]., Conclusion: Despite higher short-term mortality, octogenarians who underwent pancreatic resection showed long-term survival similar to younger patients. With careful patient screening and counselling of elderly patients, a further increase of resection rates may be combined with improved outcomes.

Background: We conducted a population-based study to investigate long-term survival in patients diagnosed with a (suspected) pancreatic adenocarcinoma., Methods: All patients diagnosed with a pancreatic adenocarcinoma or with a pathologically unverified tumour of the pancreas between 1993 and 2008 in the South of the Netherlands were selected from the Netherlands Cancer Registry (NCR). Medical charts of patients who were alive five years or longer since diagnosis were reviewed., Results: A total of 2 564 patients were included, of whom 1 365 had a pancreatic adenocarcinoma and 1 199 had a pathologically unverified pancreatic tumour. Five-year survival of patients with pathologically verified adenocarcinomas was 1.7% (24 of 1 365 patients). Twenty-one-one of these 24 long-term survivors were among the 207 cases that underwent surgical resection as initial treatment; five-year survival after resection thus being 10.1%. Half of the long-term survivors who underwent surgical resection still eventually died of recurrent disease. Five-year survival among patients with clinically suspected but microscopically unverified pancreatic tumours was 1.3% (16 of 1 199 patients). In 15 of these 16 long-term survivors the initial clinical diagnosis was revised: 14 had benign disease and one a premalignant tumour., Conclusions: Long-term survival among patients with pancreatic adenocarcinoma is extremely rare. As long-term survival in clinically suspected but pathologically unverified cancer is very unlikely, repeated fine needle aspiration or, preferably, histological biopsy is recommended in order to establish an alternative diagnosis in patients who survive longer than expected (more than 6-12 months).

Background: With evolving treatment possibilities for peritoneal metastases (PM) from colorectal cancer (CRC), adequate prognostication and patient selection for treatment becomes increasingly important. We investigated the prognostic relevance of commonly identified histological subtypes in PM of CRC (adenocarcinoma [AC], mucinous AC [MC], and signet-ring cell carcinoma [SC]), which is currently unclear., Patients and Methods: This study involved 4277 patients diagnosed with synchronous PM from CRC between 2005 and 2012 in The Netherlands. Kaplan-Meier analysis and log-rank testing were performed to estimate survival. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death., Results: Most of the CRC patients were diagnosed with AC (n = 3008; 70%), whereas MC and SC were found in 958 (22%) and 311 (7%) patients, respectively. SC was associated with the highest risk of death in colon and rectal cancer, with median survival rates of respectively, 6.6 and 6.9 months. For MC, median survival varied from 10.9 months in colon and 9.8 months in rectal cancer (P > .05). In colon cancer, MC was associated with a significantly lower risk of death compared with AC (hazard ratio, 0.9; 95% confidence interval, 0.79-0.95). In rectal cancer, no such effect was observed. AC was associated with a significantly poorer survival rate in the case of primary colonic tumor localization (7.4 months in colon vs. 10.9 months in rectal cancer)., Conclusion: Histological subtype is an important prognostic factor in patients with synchronous PM of colorectal origin. This knowledge will aid clinicians in counseling of patients and clinical decision-making regarding possible treatment options., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands., Methods: From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected., Results: Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months., Conclusion: In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A large proportion of patients with pancreatic cancer presents with metastatic disease. We conducted a population-based study to evaluate trends in treatment and survival of patients with metastatic pancreatic cancer., Methods: We included all patients diagnosed with pancreatic cancer between 1993 and 2010 in the South of the Netherlands (N=3099). Multivariable logistic regression analysis was conducted to evaluate trends in treatment with chemotherapy. Crude overall survival according to period of diagnosis was analyzed, and independent risk factors for death were identified., Results: Forty-eight percent of the patients (N=1494) were diagnosed with metastatic disease. The percentage of patients being diagnosed with metastatic disease increased during the study period from 35% in 1993-1996 to 59% in 2009-2010 (p<0.0001). Overall, 18% of these patients received chemotherapy. The prescription of palliative chemotherapy almost tripled from 10% to 27% (p<0.0001). Treatment largely depended on age, ranging from 38% among patients aged <50 years [compared to 60-69 years: adjusted odds ratio (ORadj) 2.5 (95% CI 1.4-4.2)] to 1% among patients aged ≥80 years [compared to 60-69 years: ORadj 0.04 (95% CI 0.0-0.2)]. Patients were more likely to receive chemotherapy if they had a high socioeconomic status [ORadj 2.0 (95% CI 1.3-3.1)], and if diagnosis was pathologically verified [no verification vs. verification: ORadj 0.3 (95% CI 0.2-0.5)]. The administration of chemotherapy varied widely between 10 hospitals (5-34%, p<0.0001). The median overall survival of patients with metastatic pancreatic cancer remained 9-11 weeks., Conclusion: A growing proportion of pancreatic cancer patients presented with metastatic disease. Usage of palliative chemotherapy increased over time, but median survival remained 9-11 weeks. In the near future, it should be evaluated if the recently introduced regimens have an impact on population-based survival.

Aim: To investigate whether cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is a feasible and effective option for patients with urological involvement of peritoneal carcinomatosis from colorectal cancer (CRC-PC)., Patients and Methods: The characteristics of patients with CRC-PC treated with CRS+HIPEC, with or without a urological procedure, between April 2005 and June 2013 in two tertiary Centres were analyzed., Results: Thirty-eight patients (14%) out of 267 CRC-PC patients treated with CRS+HIPEC had a urological procedure during cytoreduction. The median survival was not significantly different between patients with or without a urological procedure (26.9 versus 32.1 months, p=0.29). Severe complications occurred more in patients with a urological procedure (47% versus 20%, p<0.001). In patients with a urological procedure, the most frequent complications were gastrointestinal leakage (n=9) and intra-abdominal abscess formation (n=5)., Conclusion: Urological resections as a part of CRS+HIPEC in patients with peritoneal carcinomatosis of colorectal origin are feasible and effective. Severe complications are prevalent in these patients but survival is comparable to patients without involvement of the urinary system., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Preoperative differentiation between malignant and benign pancreatic tumors can be difficult. Consequently, a proportion of patients undergoing pancreatoduodenectomy for suspected malignancy will ultimately have benign disease. The aim of this study was to compare preoperative clinical and diagnostic characteristics of patients with unexpected benign disease after pancreatoduodenectomy with those of patients with confirmed (pre)malignant disease., Methods: We performed a multicenter retrospective cohort study in 1,629 consecutive patients undergoing pancreatoduodenectomy for suspected malignancy between 2003 and 2010 in 11 Dutch centers. Preoperative characteristics were compared in a benign:malignant ratio of 1:3. Malignant cases were selected from the entire cohort by using a random number list. A multivariable logistic regression prediction model was constructed to predict benign disease., Results: Of 107 patients (6.6 %) with unexpected benign disease after pancreatoduodenectomy, 86 fulfilled the inclusion criteria and were compared with 258 patients with (pre)malignant disease. Patients with benign disease presented more often with pain (56 vs. 38 %; P = 0.004), but less frequently with jaundice (60 vs. 80 %; P < 0.01), a pancreatic mass (13 vs. 54 %, P < 0.001), or a double duct sign on computed tomography (21 vs. 47 %; P < 0.001). In a prediction model using these parameters, only 19 % of patients with benign disease were correctly predicted, and 1.4 % of patients with malignant disease were missed., Conclusions: Nearly 7 % of patients undergoing pancreatoduodenectomy for suspected malignancy were ultimately diagnosed with benign disease. Although some preoperative clinical and imaging characteristics might indicate absence of malignancy, their discriminatory value is insufficient for clinical use.

Background: This study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients., Methods: All patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N=5671). By means of active follow-up by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years., Results: Of the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range 10-29 months). Male gender (HR=1.2, 95%CI 1.03-1.32), an advanced primary T-stage (T4 vs. T3 HR=1.6, 95%CI 1.32-1.90) and N-stage (N1 vs. N0 HR=2.8, 95%CI 2.42-3.30 and N2 vs. N0 HR=4.5, 95%CI 3.72-5.42), high-grade tumour differentiation (HR=1.4, 95%CI 1.17-1.62), and a positive (HR=2.1, 95%CI 1.68-2.71) and unknown (HR=1.7, 95%CI 1.34-2.22) resection margin were predictors for metachronous metastases., Conclusions: Different patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Primary cytoreductive surgery (CRS) and peri-operative intraperitoneal chemotherapy (PIC) is the only curative option for patients with colorectal cancer peritoneal carcinomatosis (PC). A significant proportion of patients develop peritoneal recurrence. Outcomes of patients undergoing secondary CRS and PIC for recurrent PC were examined., Methods: All patients undergoing second procedures with curative intent for recurrent appendiceal or colorectal cancer PC in three centers were included. Patients with recurrent pseudomyxoma peritonei (PMP) were excluded. Morbidity and mortality, overall survival, and disease-free survival were primary outcome parameters., Results: The study included 18 patients (13 colorectal and 5 appendiceal cancer). At primary CRS, mean Peritoneal Cancer Index (PCI) was 9.1. In 13 patients complete resection was achieved. Median time to recurrence was 14 months (range: 1-33). At secondary CRS, mean PCI was 6.3 and CRS was complete in 13 patients. There was no 30-day mortality and 1- and 2-year survival were 74% and 50%, respectively. In 14 patients a recurrence after the second procedure was diagnosed., Conclusions: A secondary CRS for recurrent colorectal or appendiceal cancer PC is safe and feasible, however, relapse is frequent. Further investigations are required to critically assess the efficacy of a secondary procedure and to define optimal patient selection criteria in the era of effective modern chemotherapy., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer., Methods/design: Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol., Discussion: The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).

Background: Carcinoma arising in a neovagina is rare., Case: A patient with an adenocarcinoma arising from a neovagina constructed with use of a sigmoid segment., Conclusion: Transplanted intestinal tissue should not be overlooked, especially in patients with an increased risk for developing metachronous malignancies.

This study aimed to identify predictors for early and very early disease recurrence in patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) resection with and without neoadjuvant therapy. Included were patients who underwent PDAC resection (2014–2016). Multivariable multinomial regression was performed to identify preoperative predictors for manifestation of recurrence within 3, 6 and 12 months after PDAC resection. 836 patients with a median follow-up of 37 (interquartile range [IQR] 30–48) months and overall survival of 18 (IQR 10-32) months were analyzed. 670 patients (80%) developed recurrence: 82 patients (10%) <3 months, 96 patients (11%) within 3–6 months and 226 patients (27%) within 6–12 months. LogCA 19–9 (OR 1.25 [95% CI 1.10–1.41]; P < 0.001) and neoadjuvant treatment (OR 0.09 [95% CI 0.01–0.68]; P = 0.02) were associated with recurrence <3 months. LogCA 19–9 (OR 1.23 [95% CI 1.10–1.38]; P < 0.001) and 0–90° venous involvement on CT imaging (OR 2.93 [95% CI 1.60–5.37]; P < 0.001) were associated with recurrence within 3–6 months. A Charlson Age Comorbidity Index ≥4 (OR 1.53 [95% CI 1.09–2.16]; P = 0.02) and logCA 19–9 (OR 1.24 [95% CI 1.14–1.35]; P < 0.001) were related to recurrence within 6–12 months. This study demonstrates preoperative predictors that are associated with the manifestation of early and very early recurrence after PDAC resection. Knowledge of these predictors can be used to guide individualized surveillance and treatment strategies. [ABSTRACT FROM AUTHOR]

The relation between type of postoperative complication and not receiving chemotherapy after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim was to investigate which patient factors and postoperative complications were associated with not receiving adjuvant chemotherapy. Patients who underwent resection (2014–2017) for PDAC were identified from the nationwide mandatory Dutch Pancreatic Cancer Audit. The association between patient-, tumor-, center-, treatment characteristics, and the risk of not receiving adjuvant chemotherapy was analyzed with multivariable logistic regression. Overall, of 1306 patients, 24% (n = 312) developed postoperative Clavien Dindo ≥3 complications. In-hospital mortality was 3.5% (n = 46). Some 433 patients (33%) did not receive adjuvant chemotherapy. Independent predictors (all p < 0.050) for not receiving adjuvant chemotherapy were older age (odds ratio (OR) 0.96), higher ECOG performance status (OR 0.57), postoperative complications (OR 0.32), especially grade B/C pancreatic fistula (OR 0.51) and post-pancreatectomy hemorrhage (OR 0.36), poor tumor differentiation grade (OR 0.62), and annual center volume of <40 pancreatoduodenectomies (OR 0.51). This study demonstrated that a third of patients do not receive chemotherapy after resection of PDAC. Next to higher age, worse performance status and lower annual surgical volume, this is mostly related to surgical complications, especially postoperative pancreatic fistula and post-pancreatectomy hemorrhage. [ABSTRACT FROM AUTHOR]

In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact hereof has not been assessed in nationwide cohort studies. This population-based study aimed to investigate nationwide trends in incidence, treatment and survival of PDAC. Patients with PDAC (1997–2016) were included from the Netherlands Cancer Registry. Results were categorised by treatment and by period of diagnosis (1997–2000, 2001–2004, 2005–2008, 2009–2012 and 2013–2016). Kaplan–Meier survival analysis was used to calculate overall survival. In a national cohort of 36,453 patients with PDAC, the incidence increased from 12.1 (1997–2000) to 15.3 (2013–2016) per 100,000 (p < 0.001), whereas median overall survival increased from 3.1 to 3.8 months (p < 0.001). Over time, the resection rate doubled (8.3%–16.6%, p-trend<0.001), more patients received adjuvant chemotherapy (3.0%–56.2%, p-trend<0.001) and 3-year overall survival following resection increased (16.9%–25.4%, p < 0.001). Over time, the proportion of patients with metastatic disease who received palliative chemotherapy increased from 5.3% to 16.1% (p-trend<0.001), whereas 1-year survival improved from 13.3% to 21.2% (p < 0.001). The proportion of patients who only received supportive care decreased from 84% to 61% (p-trend<0.001). The incidence of PDAC increased in the past two decades. Resection rates and use of adjuvant or palliative chemotherapy increased with improved survival in these patients. In all patients with PDAC, however, the survival benefit of 3 weeks is negligible because the majority of patients only received supportive care. • The incidence of pancreatic ductal adenocarcinoma increased from 1997 to 2016. • Resection rates and use of adjuvant or palliative chemotherapy increased. • The majority of patients still received supportive care only. • Survival improved in patients who underwent resection or systemic treatment. • The survival of all patients improved with only 3 weeks. [ABSTRACT FROM AUTHOR]