This thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section... Show moreThis thesis consists of two sections. In Section I, (pre)clinical research investigating novel targets for pre- and intraoperative molecular imaging of pancreatic cancer are discussed. In Section II, various studies are described which lay the groundwork for further investigation into response monitoring and prediction in rectal cancer using various imaging modalities. Show less
BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic... Show moreBackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and & LE; 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), irinotecan 150 mg/m(2) at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m(2)). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. Show less
Introduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important... Show moreIntroduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer. Methods: Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer). Results: In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/ 679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88. Discussion: This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoad-juvant ipilimumab plus... Show moreBackground: Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoad-juvant ipilimumab plus nivolumab induces high pathologic response rates and an impressive relapse-free survival in patients with nodal macroscopic stage III melanoma. Whether primary site melanoma and in-transit metastases respond similarly to lymph node metastases with neoadjuvant immunotherapy is largely unknown. Such data would clarify whether surgical excision of these melanoma lesions should be performed before neoadjuvant therapy or whether it could be deferred and performed in conjunction with lymphadenectomy following neoadjuvant immunotherapy. Patients: Patients with synchronous clinical stage III melanoma were identified from the OpA-CIN, OpACIN-neo and PRADO neoadjuvant trials, where all patients were treated with ipi-limumab plus nivolumab. An additional case treated outside those clinical trials was included. Results: Seven patients were identified; six patients had a concordant response in primary site melanoma lesions or in-transit metastasis and the lymph node metastases. One patient had concordant progression in both the primary and nodal tumour lesions and developed stage IV disease during neoadjuvant treatment, and thus, no resection was performed. Conclusion: Pathologic response following neoadjuvant ipilimumab plus nivolumab in pri-mary site melanoma lesions or in-transit metastasis is concordant with a response in the lymph node metastases, indicating that there may be no need to perform upfront surgery to these melanoma lesions prior to neoadjuvant treatment. (c) 2021 Elsevier Ltd. All rights reserved. Show less
Pancreatic cancer has a dismal prognosis, with a 5-year survival of less than 9%. Consequently, pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of... Show morePancreatic cancer has a dismal prognosis, with a 5-year survival of less than 9%. Consequently, pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of cancer-related death in the Western World by 2030. Complete surgical resection offers the only hope for long-term survival in these patients. However, even among the fortunate to undergo curative-intent resection, recurrence rates remains high, indicating that there is a subgroup of patient who already harbor microscopic metastases at diagnosis. At present, the majority of radiographically resectable pancreatic cancer patients undergo immediate pancreatic cancer surgery followed by chemotherapy instead of receiving chemoradiation before the surgery (also known as preoperative or neoadjuvant therapy), as is standard of care for many other gastrointestinal malignancies. The results of this thesis demonstrate that neoadjuvant therapy was association with increased overall survival and quality-adjusted life expectancy compared to surgery without neoadjuvant therapy in pancreatic cancer patients. In addition, the results of this thesis demonstrate that molecular marker, including integrin αvβ6, CEA, EGFR, and uPAR, may be used to identify patients who are at high risk of early recurrence after pancreatic surgery and may benefit most from neoadjuvant therapy. Show less
Valk, M.J.M. van der; Vuijk, F.A.; Putter, H.; Velde, C.J.H. van de; Beets, G.L.; Hilling, D.E. 2019
Introduction: The aim of this study is to provide insight in accuracy of diagnosing, current treatment and survival in patients with resectable esophageal and gastric neuroendocrine- and mixed... Show moreIntroduction: The aim of this study is to provide insight in accuracy of diagnosing, current treatment and survival in patients with resectable esophageal and gastric neuroendocrine- and mixed adenoneuroendocrine carcinomas (NEC, MANEC).Methods: All patients with esophageal or gastric (MA)NEC, who underwent surgical resection between 2006 and 2016, were identified from the Dutch national registry for histo-and cytopathology (PALGA). Patients with a neuroendocrine tumor lower than grade 3 were excluded. Data on patients, treatment and outcomes were retrieved from the patient records. Diagnosis by endoscopic biopsy was compared with diagnosis by resection specimen. Kaplan Meier survival analysis was performed.Results: A total of 49 patients were identified in 25 hospitals, including 21 patients with esophageal (MA)NEC and 26 patients with gastric (MA)NEC on resection specimen. Biopsy diagnosis of (MA)NEC was correct in 23/27 patients. However, 20/47 patients with definitive diagnosis of (MA)NEC, were misdiagnosed on biopsy. Neoadjuvant therapy was administered in 13 (62%) esophageal (MA)NEC5 and 12 (46%) gastric (MA)NECs. Survival curves were similar with and without neoadjuvant therapy. One (4.8%) esophageal (MA)NEC and 4 (15%) gastric (MA)NEC5 died within 90 days postoperatively. For esophageal (MA)NEC the median overall survival (OS) after surgery was 37 months and 1-, 3- and 5-year OS were 71%, 50% and 35%, respectively. For gastric (MA)NEC, the median OS was 23 months and 1-, 3- and 5-year OS were 62%, 50% and 39%, respectively.Conclusion: Localized esophageal and gastric (MA)NEC are often misdiagnosed on endoscopic biopsies. After resection, long-term survival was achieved in respectively 35% and 39% of patients. (C) 2018 Published by Elsevier Ltd. Show less
Purpose: To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy ... Show morePurpose: To explore and evaluate the potential value of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in oesophageal cancer.Material and methods: Twenty-six patients underwent DCE-MRI before, during (week 2-3) and after nCRT, but before surgery (pre/per/post, respectively). Histopathologic tumour regression grade (TRG) was assessed after oesophagectomy. Tumour area-under-the-concentration time curve (AUC), time-to peak (TTP) and slope were calculated. The ability of these DCE-parameters to distinguish good responders (GR, TRG 1-2) from poor responders (noGR, TRG >= 3), and pathologic complete responders (pCR) from no-pCR was assessed.Results: Twelve patients (48%) showed GR of which 8 patients (32%) pCR. Analysis of AUC change throughout treatment, AUC(per-pre), was most predictive for GR, at a threshold of 22.7% resulting in a sensitivity of 92%, specificity of 77%, PPV of 79%, and a NPV of .91%. AUC(post-pre) was most predictive for pCR, at a threshold of -24.6% resulting in a sensitivity of 83%, specificity of 88%, PPV of 71%, and a NPV of 93%. TTP and slope were not associated with pathologic response.Conclusions: This study demonstrates that changes in AUC throughout treatment are promising for prediction of histopathologic response to nCRT for oesophageal cancer. (C) 2016 Elsevier Ireland Ltd. All rights reserved. Show less
Purpose: To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer... Show morePurpose: To explore the value of diffusion-weighted magnetic resonance imaging (DW-MRI) for the prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer.Material and methods: In 20 patients receiving nCRT for esophageal cancer DW-MRI scanning was performed before nCRT, after 8-13 fractions, and before surgery. The median tumor apparent diffusion coefficient (ADC) was determined at these three time points. The predictive potential of initial tumor ADC, and change in ADC (Delta ADC) during and after treatment for pathologic complete response (pathCR) and good response were assessed. Good response was defined as pathCR or near-pathCR (tumor regression grade [TRG] 1 or 2).Results: A pathCR after nCRT was found in 4 of 20 patients (20%), and 8 patients (40%) showed a good response to nCRT. The Delta ADC(during) was significantly higher in pathCR vs. non-pathCR patients (34.6% +/- 10.7% [mean +/- SD] vs. 14.0% +/- 13.1%, p = 0.016), as well as in good vs. poor responders (30.5% +/- 8.3% vs. 9.5% +/- 12.5%, p = 0.002). The Delta ADC(during) was predictive of residual cancer at a threshold of 29% (sensitivity of 100%, specificity of 75%, PPV of 94%, and NPV of 100%), and for poor pathologic response at a threshold of 21% (sensitivity of 82%, specificity of 100%, PPV of 100%, and NPV of 80%).Conclusions: In this exploratory study, the treatment-induced change in ADC during the first 2-3 weeks of nCRT for esophageal cancer seemed highly predictive of histopathologic response. Larger series are warranted to verify these results. (C) 2015 Elsevier Ireland Ltd. All rights reserved. Show less
