Publications by authors named "Arend G Aalbers"

32 Publications

Risk of metachronous peritoneal metastases in patients with pT4a versus pT4b colon cancer: An international multicentre cohort study.

Eur J Surg Oncol 2021 Sep 15;47(9):2405-2413. Epub 2021 May 15.

Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Centre Amsterdam, Amsterdam, the Netherlands. Electronic address:

Introduction: With evolving treatment strategies aiming at prevention or early detection of metachronous peritoneal metastases (PM), identification of high-risk colon cancer patients becomes increasingly important. This study aimed to evaluate differences between pT4a (peritoneal penetration) and pT4b (invasion of other organs/structures) subcategories regarding risk of PM and other oncological outcomes.

Materials And Methods: From eight databases deriving from four countries, patients who underwent curative intent treatment for pT4N0-2M0 primary colon cancer were included. Primary outcome was the 5-year metachronous PM rate assessed by Kaplan-Meier analysis. Independent predictors for metachronous PM were identified by Cox regression analysis. Secondary endpoints included 5-year local and distant recurrence rates, and 5-year disease free and overall survival (DFS, OS).

Results: In total, 665 patients with pT4a and 187 patients with pT4b colon cancer were included. Median follow-up was 38 months (IQR 23-60). Five-year PM rate was 24.7% and 12.2% for pT4a and pT4b categories, respectively (p = 0.005). Independent predictors for metachronous PM were female sex, right-sided colon cancer, peritumoral abscess, pT4a, pN2, R1 resection, signet ring cell histology and postoperative surgical site infections. Five-year local recurrence rate was 14% in both pT4a and pT4b cancer (p = 0.138). Corresponding five-year distant metastases rates were 35% and 28% (p = 0.138). Five-year DFS and OS were 54% vs. 62% (p = 0.095) and 63% vs. 68% (p = 0.148) for pT4a vs. pT4b categories, respectively.

Conclusion: Patients with pT4a colon cancer have a higher risk of metachronous PM than pT4b patients. This observation has important implications for early detection and future adjuvant treatment strategies.
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http://dx.doi.org/10.1016/j.ejso.2021.05.009DOI Listing
September 2021

Perioperative Systemic Therapy vs Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Alone for Resectable Colorectal Peritoneal Metastases: A Phase 2 Randomized Clinical Trial.

JAMA Surg 2021 Aug;156(8):710-720

Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

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.
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http://dx.doi.org/10.1001/jamasurg.2021.1642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135056PMC
August 2021

Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer: A Review.

JAMA Oncol 2021 Aug;7(8):1231-1238

Center for Gynecologic Oncology Amsterdam, The Netherlands Cancer Institute, Amsterdam.

Importance: The peritoneal surface is a common site of disease in ovarian and colorectal cancer. Peritoneal metastases carry a poor prognosis, despite maximal therapeutic efforts, including surgical removal of tumor deposits and intravenous chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative procedure that delivers chemotherapy directly into the abdominal cavity, leading to high intracellular drug concentration at the peritoneal surface. This review describes the current knowledge regarding the mechanism of action, safety, and efficacy of HIPEC in the treatment of peritoneal metastases from epithelial ovarian and colorectal cancers and explores current knowledge gaps.

Observations: Toxic effects of HIPEC are limited. Evidence from a randomized trial shows improved recurrence-free and overall survival after HIPEC in patients with ovarian cancer who are ineligible for primary cytoreductive surgery (CRS). The effect of HIPEC for patients with ovarian cancer undergoing primary CRS or CRS for recurrent disease has not yet been determined, and results of ongoing trials must be awaited. A recent study in patients with peritoneal metastases from colorectal cancer did not show a benefit of HIPEC when added to perioperative chemotherapy.

Conclusions And Relevance: Based on available evidence, various international guidelines include the option to add HIPEC to interval CRS for patients with stage III ovarian cancer. The role of HIPEC in colorectal cancer is less well defined. Future studies will need to tailor patient selection, timing, and optimal regimens of HIPEC to improve the effectiveness of this specialized treatment in ovarian, colorectal, and other tumor types.
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http://dx.doi.org/10.1001/jamaoncol.2021.0580DOI Listing
August 2021

Perineal wound closure using gluteal turnover flap or primary closure after abdominoperineal resection for rectal cancer: study protocol of a randomised controlled multicentre trial (BIOPEX-2 study).

BMC Surg 2020 Jul 23;20(1):164. Epub 2020 Jul 23.

Department of Surgery, OLVG Hospital, Amsterdam, The Netherlands.

Background: Abdominoperineal resection (APR) for rectal cancer is associated with high morbidity of the perineal wound, and controversy exists about the optimal closure technique. Primary perineal wound closure is still the standard of care in the Netherlands. Biological mesh closure did not improve wound healing in our previous randomised controlled trial (BIOPEX-study). It is suggested, based on meta-analysis of cohort studies, that filling of the perineal defect with well-vascularised tissue improves perineal wound healing. A gluteal turnover flap seems to be a promising method for this purpose, and with the advantage of not having a donor site scar. The aim of this study is to investigate whether a gluteal turnover flap improves the uncomplicated perineal wound healing after APR for rectal cancer.

Methods: Patients with primary or recurrent rectal cancer who are planned for APR will be considered eligible in this multicentre randomised controlled trial. Exclusion criteria are total exenteration, sacral resection above S4/S5, intersphincteric APR, biological mesh closure of the pelvic floor, collagen disorders, and severe systemic diseases. A total of 160 patients will be randomised between gluteal turnover flap (experimental arm) and primary closure (control arm). The total follow-up duration is 12 months, and outcome assessors and patients will be blinded for type of perineal wound closure. The primary outcome is the percentage of uncomplicated perineal wound healing on day 30, defined as a Southampton wound score of less than two. Secondary outcomes include time to perineal wound closure, incidence of perineal hernia, the number, duration and nature of the complications, re-interventions, quality of life and urogenital function.

Discussion: The uncomplicated perineal wound healing rate is expected to increase from 65 to 85% by using the gluteal turnover flap. With proven effectiveness, a quick implementation of this relatively simple surgical technique is expected to take place.

Trial Registration: The trial was retrospectively registered at Clinicaltrials.gov NCT04004650 on July 2, 2019.
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http://dx.doi.org/10.1186/s12893-020-00823-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376711PMC
July 2020

Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus Surgery Without HIPEC for Goblet-Cell Carcinoids and Mixed Adenoneuroendocrine Carcinomas: Propensity Score-Matched Analysis of Centers in the Netherlands and Belgium.

Clin Colorectal Cancer 2020 09 30;19(3):e87-e99. Epub 2020 Jan 30.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

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.
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http://dx.doi.org/10.1016/j.clcc.2020.01.002DOI Listing
September 2020

Association of Image-Guided Navigation With Complete Resection Rate in Patients With Locally Advanced Primary and Recurrent Rectal Cancer: A Nonrandomized Controlled Trial.

JAMA Netw Open 2020 07 1;3(7):e208522. Epub 2020 Jul 1.

Department of Surgical Oncology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

Importance: The percentage of tumor-positive surgical resection margin rates in patients treated for locally advanced primary or recurrent rectal cancer is high. Image-guided navigation may improve complete resection rates.

Objective: To ascertain whether image-guided navigation during rectal cancer resection improves complete resection rates compared with surgical procedures without navigation.

Design, Setting, And Participants: This prospective single-center nonrandomized controlled trial was conducted at the Netherlands Cancer Institute-Antoni van Leeuwenhoek in Amsterdam, the Netherlands. The prospective or navigation cohort included adult patients with locally advanced primary or recurrent rectal cancer who underwent resection with image-guided navigation between February 1, 2016, and September 30, 2019, at the tertiary referral hospital. Clinical results of this cohort were compared with results of the historical cohort, which was composed of adult patients who received rectal cancer resection without image-guided navigation between January 1, 2009, and December 31, 2015.

Intervention: Rectal cancer resection with image-guided navigation.

Main Outcomes And Measures: The primary end point was the complete resection rate, measured by the amount of tumor-negative resection margin rates. Secondary outcomes were safety and usability of the system. Safety was evaluated by the number of navigation system-associated surgical adverse events. Usability was assessed from responses to a questionnaire completed by the participating surgeons after each procedure.

Results: In total, 33 patients with locally advanced or recurrent rectal cancer were included (23 men [69.7%]; median [interquartile range] age at start of treatment, 61 [55.0-69.0] years). With image-guided navigation, a radical resection (R0) was achieved in 13 of 14 patients (92.9%; 95% CI, 66.1%-99.8%) after primary resection of locally advanced tumors and in 15 of 19 patients (78.9%; 95% CI, 54.4%-94.0%) after resection of recurrent rectal cancer. No navigation system-associated complications occurred before or during surgical procedures. In the historical cohort, 142 patients who underwent resection without image-guided navigation were included (95 men [66.9%]; median [interquartile range] age at start of treatment, 64 [55.0-70.0] years). In these patients, an R0 resection was accomplished in 85 of 101 patients (84.2%) with locally advanced rectal cancer and in 20 of 41 patients (48.8%) with recurrent rectal cancer. A significant difference was found between the navigation and historical cohorts after recurrent rectal cancer resection (21.1% vs 51.2%; P = .047). For locally advanced primary tumor resection, the difference was not significant (7.1% vs 15.8%; P = .69). Surgeons stated in completed questionnaires that the navigation system improved decisiveness and helped with tumor localization.

Conclusions And Relevance: Findings of this study suggest that image-guided navigation used during rectal cancer resection is safe and intuitive and may improve tumor-free resection margin rates in recurrent rectal cancer.

Trial Registration: Netherlands Trial Register Identifier: NTR7184.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.8522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344384PMC
July 2020

Accurate surgical navigation with real-time tumor tracking in cancer surgery.

NPJ Precis Oncol 2020 8;4. Epub 2020 Apr 8.

1Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

In the past decades, image-guided surgery has evolved rapidly. In procedures with a relatively fixed target area, like neurosurgery and orthopedics, this has led to improved patient outcomes. In cancer surgery, intraoperative guidance could be of great benefit to secure radical resection margins since residual disease is associated with local recurrence and poor survival. However, most tumor lesions are mobile with a constantly changing position. Here, we present an innovative technique for real-time tumor tracking in cancer surgery. In this study, we evaluated the feasibility of real-time tumor tracking during rectal cancer surgery. The application of real-time tumor tracking using an intraoperative navigation system is feasible and safe with a high median target registration accuracy of 3 mm. This technique allows oncological surgeons to obtain real-time accurate information on tumor location, as well as critical anatomical information. This study demonstrates that real-time tumor tracking is feasible and could potentially decrease positive resection margins and improve patient outcome.
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http://dx.doi.org/10.1038/s41698-020-0115-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142120PMC
April 2020

Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.

Nat Med 2020 04 6;26(4):566-576. Epub 2020 Apr 6.

Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8PD-1 T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.
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http://dx.doi.org/10.1038/s41591-020-0805-8DOI Listing
April 2020

Extent of Peritoneal Metastases on Preoperative DW-MRI is Predictive of Disease-Free and Overall Survival for CRS/HIPEC Candidates with Colorectal Cancer.

Ann Surg Oncol 2020 Sep 1;27(9):3516-3524. Epub 2020 Apr 1.

Department of Radiology, Antoni van Leeuwenhoek-Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objective: The aim of this study was to determine whether the extent of peritoneal metastases (PMs) on preoperative diffusion-weighted magnetic resonance imaging (DW-MRI) can be used as a biomarker of disease-free and overall survival in patients with colorectal cancer who are considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

Methods: For this retrospective cohort study, patients with PMs considered for CRS/HIPEC who underwent DW-MRI for preoperative staging in 2016-2017 were included. The DW-MRI protocol consisted of diffusion-weighted, T2-weighted, and pre- and post-gadolinium T1-weighted imaging of the chest, abdomen, and pelvis. DW-MRI images were evaluated by two independent readers to determine the extent of PMs represented by the Peritoneal Cancer Index (MRI-PCI), as well as extraperitoneal metastases. Cox regression and Kaplan-Meier analysis was performed to determine the prognostic value of DW-MRI for overall and disease-free survival.

Results: Seventy-eight patients were included. CRS/HIPEC was planned for 53 patients and completed in 50 patients (60.5%). Median follow-up after DW-MRI was 23 months (interquartile range 13-24). The MRI-PCI of both readers showed prognostic value for overall survival, independently of whether R1 resection was achieved (hazard ratio [HR] 1.06-1.08; p < 0.05). For the patients who received successful CRS/HIPEC, the MRI-PCI also showed independent prognostic value for disease-free survival for both readers (HR 1.09-1.10; p < 0.05).

Conclusion: The extent of PMs on preoperative DW-MRI is an independent predictor of overall and disease-free survival and should therefore be considered as a non-invasive prognostic biomarker.
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http://dx.doi.org/10.1245/s10434-020-08416-7DOI Listing
September 2020

Diagnostic Laparoscopy and Abdominal Cytology Reliably Detect Peritoneal Metastases in Patients with Urachal Adenocarcinoma.

Ann Surg Oncol 2020 Jul 12;27(7):2468-2475. Epub 2020 Feb 12.

Department of Surgical Oncology (Urology), The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.

Background: Urachal adenocarcinoma (UrAC) is a rare malignancy that can cause peritoneal metastases (PM). Analogous to other enteric malignancies, selected patients with limited PM of UrAC can be treated by cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC).

Objective: The aim of this study was to address the value of diagnostic laparoscopy (DLS) and abdominal cytology (ACyt) for the detection and evaluation of the extent of PM in patients with UrAC.

Methods: A consecutive series of cN0M0 patients with UrAC who underwent DLS with or without ACyt at a tertiary referral center between 2000 and 2018 was assessed. Patients were staged with computed tomography (CT) and/or positron emission tomography (PET)/CT or bone scan. DLS was performed to rule out PM and to evaluate the extent and resectability of PM if seen on imaging. Sensitivity and specificity values were calculated for imaging, DLS, ACyt, and the combination of DLS and ACyt.

Results: Thirty-two patients with UrAC underwent DLS. ACyt was obtained in 19 patients. Four patients had suspicion of PM on imaging. In the 28 patients who were PM-negative on imaging, DLS and ACyt revealed PM in 6 (21%) patients, of whom 5 had macroscopically visible PM; 1 patient had positive ACyt without visible PM. Sensitivity of combined DLS/ACyt for the detection of PM was 91%, with a specificity of 100%, whereas sensitivity of imaging was 36%. DLS correctly predicted resectability in all patients.

Conclusion: Combined DLS/ACyt proved an effective tool to detect occult PM and to evaluate the extent of PM to select UrAC patients for possible treatment with CRS/HIPEC.
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http://dx.doi.org/10.1245/s10434-020-08206-1DOI Listing
July 2020

Using Diffuse Reflectance Spectroscopy to Distinguish Tumor Tissue From Fibrosis in Rectal Cancer Patients as a Guide to Surgery.

Lasers Surg Med 2020 09 3;52(7):604-611. Epub 2019 Dec 3.

Department of Surgery, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.

Background And Objectives: In patients with rectal cancer who received neoadjuvant (chemo)radiotherapy, fibrosis is induced in and around the tumor area. As tumors and fibrosis have similar visual and tactile feedback, they are hard to distinguish during surgery. To prevent positive resection margins during surgery and spare healthy tissue, it would be of great benefit to have a real-time tissue classification technology that can be used in vivo.

Study Design/materials And Methods: In this study diffuse reflectance spectroscopy (DRS) was evaluated for real-time tissue classification of tumor and fibrosis. DRS spectra of fibrosis and tumor were obtained on excised rectal specimens. After normalization using the area under the curve, a support vector machine was trained using a 10-fold cross-validation.

Results: Using spectra of pure tumor tissue and pure fibrosis tissue, we obtained a mean accuracy of 0.88. This decreased to a mean accuracy of 0.61 when tumor measurements were used in which a layer of healthy tissue, mainly fibrosis, was present between the tumor and the measurement surface.

Conclusion: It is possible to distinguish pure fibrosis from pure tumor. However, when the measurements on tumor also involve fibrotic tissue, the classification accuracy decreases. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23196DOI Listing
September 2020

Adjuvant hyperthermic intraperitoneal chemotherapy in patients with locally advanced colon cancer (COLOPEC): a multicentre, open-label, randomised trial.

Lancet Gastroenterol Hepatol 2019 10 29;4(10):761-770. Epub 2019 Jul 29.

Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands. Electronic address:

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) and leucovorin (20 mg/m) delivered intravenously followed by intraperitoneal delivery of oxaliplatin (460 mg/m) 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.
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http://dx.doi.org/10.1016/S2468-1253(19)30239-0DOI Listing
October 2019

Cost Effectiveness of Interval Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy in Stage III Ovarian Cancer on the Basis of a Randomized Phase III Trial.

J Clin Oncol 2019 08 28;37(23):2041-2050. Epub 2019 Jun 28.

1The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Purpose: In the randomized open-label phase III OVHIPEC trial, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery (CRS) improved recurrence-free and overall survival in patients with stage III ovarian cancer. We studied the cost effectiveness of the addition of HIPEC to interval CRS in patients with ovarian cancer.

Patients And Methods: We constructed a Markov health-state transition model to measure costs and clinical outcomes. Transition probabilities were derived from the OVHIPEC trial by fitting survival distributions. Incremental cost-effectiveness ratio (ICER), expressed as euros per quality-adjusted life-year (QALY), was calculated from a Dutch societal perspective, with a time horizon of 10 years. Univariable and probabilistic sensitivity analyses were conducted to evaluate the decision uncertainty.

Results: Total health care costs were €70,046 (95% credibility interval [CrI], €64,016 to €76,661) for interval CRS compared with €85,791 (95% CrI, €78,766 to €93,935) for interval CRS plus HIPEC. The mean QALY in the interval CRS group was 2.12 (95% CrI, 1.66 to 2.64 QALYs) and 2.68 (95% CrI, 2.11 to 3.28 QALYs) in the interval CRS plus HIPEC group. The ICER amounted to €28,299/QALY. In univariable sensitivity analysis, the utility of recurrence-free survival and the number of days in the hospital affected the calculated ICER most.

Conclusion: On the basis of the trial data, treatment with interval CRS and HIPEC in patients with stage III ovarian cancer was accompanied by a substantial gain in QALYs. The ICER is below the willingness-to-pay threshold in the Netherlands, indicating interval CRS and HIPEC is cost effective for this patient population. These results lend additional support for reimbursing the costs of treating these patients with interval CRS and HIPEC in countries with comparable health care systems.
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http://dx.doi.org/10.1200/JCO.19.00594DOI Listing
August 2019

Treatment and survival of locally recurrent rectal cancer: A cross-sectional population study 15 years after the Dutch TME trial.

Eur J Surg Oncol 2019 Nov 17;45(11):2059-2069. Epub 2019 Jun 17.

Netherlands Cancer Institute-Antoni van Leeuwenhoek, Department of Surgery, Amsterdam, the Netherlands.

Introduction: Optimized treatment of primary rectal cancer might have influenced treatment characteristics and outcome of locally recurrent rectal cancer (LRRC). Subgroup analysis of the Dutch TME trial showed that preoperative radiotherapy (PRT) for the primary tumour was an independent poor prognostic factor after diagnosis of LRRC. This cross-sectional population study aimed to evaluate treatment and overall survival (OS) of LRRC patients, stratified for prior preoperative radiotherapy (PRT) and intention of treatment of LRRC.

Methods: All patients developing LRRC were selected from a collaborative Snapshot study on 2095 surgically treated rectal cancer patients from 71 Dutch hospitals in the year 2011. Cox proportional hazard analysis was performed to determine predictors for OS.

Results: A total of 107 LRRC patients (5.1%) were included, of whom 88 (82%) underwent PRT for their primary tumour. LRRC was treated with initial curative intent in 31 patients (29%), with eventual resection in 20 patients (19%). Median OS was 22 and 8 months after curative and palliative intent treatment, respectively (p < 0.001). Initial CRM positivity and palliative intent treatment were associated with worse OS after LRRC, while prior PRT was not.

Conclusions: This cross-sectional study revealed that rectal cancer patients, who underwent curative resection in the Netherlands in 2011 and subsequently developed local recurrence, were amenable for again curative intent treatment in 29%, with a corresponding median survival of 22 months. Prior PRT was not significantly associated with survival after diagnosis of LRRC.
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http://dx.doi.org/10.1016/j.ejso.2019.06.016DOI Listing
November 2019

Perioperative systemic therapy and cytoreductive surgery with HIPEC versus upfront cytoreductive surgery with HIPEC alone for isolated resectable colorectal peritoneal metastases: protocol of a multicentre, open-label, parallel-group, phase II-III, randomised, superiority study (CAIRO6)

BMC Cancer 2019 04 25;19(1):390. Epub 2019 Apr 25.

Department of Surgery, University Medical Centre Groningen, PO Box 30001, 9700 RB, Groningen, RB, Netherlands.

Background: Upfront cytoreductive surgery with HIPEC (CRS-HIPEC) is the standard treatment for isolated resectable colorectal peritoneal metastases (PM) in the Netherlands. This study investigates whether addition of perioperative systemic therapy to CRS-HIPEC improves oncological outcomes.

Methods: This open-label, parallel-group, phase II-III, randomised, superiority study is performed in nine Dutch tertiary referral centres. Eligible patients are adults who have a good performance status, histologically or cytologically proven resectable PM of a colorectal adenocarcinoma, no systemic colorectal metastases, no systemic therapy for colorectal cancer within six months prior to enrolment, and no previous CRS-HIPEC. Eligible patients are randomised (1:1) to perioperative systemic therapy and CRS-HIPEC (experimental arm) or upfront CRS-HIPEC alone (control arm) by using central randomisation software with minimisation stratified by a peritoneal cancer index of 0-10 or 11-20, metachronous or synchronous PM, previous systemic therapy for colorectal cancer, and HIPEC with oxaliplatin or mitomycin C. At the treating physician's discretion, perioperative systemic therapy consists of either four 3-weekly neoadjuvant and adjuvant cycles of capecitabine with oxaliplatin (CAPOX), six 2-weekly neoadjuvant and adjuvant cycles of 5-fluorouracil/leucovorin with oxaliplatin (FOLFOX), or six 2-weekly neoadjuvant cycles of 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) followed by four 3-weekly (capecitabine) or six 2-weekly (5-fluorouracil/leucovorin) adjuvant cycles of fluoropyrimidine monotherapy. Bevacizumab is added to the first three (CAPOX) or four (FOLFOX/FOLFIRI) neoadjuvant cycles. The first 80 patients are enrolled in a phase II study to explore the feasibility of accrual and the feasibility, safety, and tolerance of perioperative systemic therapy. If predefined criteria of feasibility and safety are met, the study continues as a phase III study with 3-year overall survival as primary endpoint. A total of 358 patients is needed to detect the hypothesised 15% increase in 3-year overall survival (control arm 50%; experimental arm 65%). Secondary endpoints are surgical characteristics, major postoperative morbidity, progression-free survival, disease-free survival, health-related quality of life, costs, major systemic therapy related toxicity, and objective radiological and histopathological response rates.

Discussion: This is the first randomised study that prospectively compares oncological outcomes of perioperative systemic therapy and CRS-HIPEC with upfront CRS-HIPEC alone for isolated resectable colorectal PM.

Trial Registration: Clinicaltrials.gov/ NCT02758951 , NTR/ NTR6301 , ISRCTN/ ISRCTN15977568 , EudraCT/ 2016-001865-99 .
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http://dx.doi.org/10.1186/s12885-019-5545-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485075PMC
April 2019

Long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal metastases of urachal cancer.

Eur J Surg Oncol 2019 Sep 1;45(9):1740-1744. Epub 2019 Apr 1.

Department of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Electronic address:

Introduction: Urachal adenocarcinoma (UrAC) is a rare malignancy arising from persistent urachal remnants, which can cause peritoneal metastases (PM). Currently, patients with this stage UrAC are considered beyond cure. Our objective is to report long-term oncological outcome after cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with PM of urachal adenocarcinoma (UrAC).

Materials And Methods: We identified 55 patients with UrAC treated at our hospital between 1994 and 2017. Patients were staged with CT, bone scintigraphy and/or PET/CT. From 2001 on, cN0M0 patients underwent staging laparoscopy. Ten patients had PM and were treated with CRS/HIPEC; 35 showed no metastases and underwent local treatment; 10 had distant metastases and received palliative chemotherapy. Disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and log-rank tests. Postoperative complications represent a secondary outcome.

Results: The median follow-up was 96.8 months. Of the CRS/HIPEC patients, 5 (50%) developed a recurrence; 4 (40%) died of disease. The 2-yr and 5-yr DSS after CRS/HIPEC were 66.7% and 55.6%, respectively. DSS of the CRS/HIPEC patients did not significantly differ from DSS of patients without metastases who only underwent curative local treatment and was superior to patients with distant metastases (P = 0.012). The overall complication rate after CRS/HIPEC was 60%. Major complications (Clavien 3) constituted 20%. The study is limited by its retrospective nature and the small sample size.

Conclusion: CRS/HIPEC demonstrates satisfactory long-term oncological outcome for patients with PM of UrAC. It may be offered as a potentially curative treatment option for this group of patients.
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http://dx.doi.org/10.1016/j.ejso.2019.03.034DOI Listing
September 2019

Second and third look laparoscopy in pT4 colon cancer patients for early detection of peritoneal metastases; the COLOPEC 2 randomized multicentre trial.

BMC Cancer 2019 Mar 21;19(1):254. Epub 2019 Mar 21.

Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, PO Box 22660, 1105 AZ, Amsterdam, the Netherlands.

Background: Approximately 20-30% of patients with pT4 colon cancer develop metachronous peritoneal metastases (PM). Due to restricted accuracy of imaging modalities and absence of early symptoms, PM are often detected at a stage in which only a quarter of patients are eligible for curative intent treatment. Preliminary findings of the COLOPEC trial (NCT02231086) revealed that PM were already detected during surgical re-exploration within two months after primary resection in 9% of patients with pT4 colon cancer. Therefore, second look diagnostic laparoscopy (DLS) to detect PM at a subclinical stage may be considered an essential component of early follow-up in these patients, although this needs confirmation in a larger patient cohort. Furthermore, a third look DLS after a negative second look DLS might be beneficial for detection of PM occurring at a later stage.

Methods: The aim of this study is to determine the yield of second look DLS and added value of third look DLS after negative second look DLS in detecting occult PM in pT4N0-2 M0 colon cancer patients after completion of primary treatment. Patients will undergo an abdominal CT at 6 months postoperative, followed by a second look DLS within 1 month if no PM or other metastases not amenable for local treatment are detected. Patients without PM will subsequently be randomized between routine follow-up including 18 months abdominal CT, or an experimental arm with a third look DLS provided that PM or incurable metastases are absent at the 18 months abdominal CT. Primary endpoint is the proportion of PM detected after a negative second look DLS and will be determined at 20 months postoperative.

Discussion: Second look DLS is supposed to result in 10% occult PM, and third look DLS after negative second look DLS is expected to detect an additional 10% of PM compared to routine follow-up alone in patients with pT4 colon cancer. Detection of PM at an early stage will likely increase the proportion of patients eligible for curative intent treatment and subsequently improve survival, given the uniformly reported direct association between the extent of peritoneal disease and survival.

Trial Registration: ClinicalTrials.gov: NCT03413254 , January 2018.
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http://dx.doi.org/10.1186/s12885-019-5408-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429794PMC
March 2019

Hyperspectral imaging for tissue classification, a way toward smart laparoscopic colorectal surgery.

J Biomed Opt 2019 01;24(1):1-9

Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Department of Surgery, Amsterdam, The Netherlands.

In the last decades, laparoscopic surgery has become the gold standard in patients with colorectal cancer. To overcome the drawback of reduced tactile feedback, real-time tissue classification could be of great benefit. In this ex vivo study, hyperspectral imaging (HSI) was used to distinguish tumor tissue from healthy surrounding tissue. A sample of fat, healthy colorectal wall, and tumor tissue was collected per patient and imaged using two hyperspectral cameras, covering the wavelength range from 400 to 1700 nm. The data were randomly divided into a training (75%) and test (25%) set. After feature reduction, a quadratic classifier and support vector machine were used to distinguish the three tissue types. Tissue samples of 32 patients were imaged using both hyperspectral cameras. The accuracy to distinguish the three tissue types using both hyperspectral cameras was 0.88 (STD  =  0.13) on the test dataset. When the accuracy was determined per patient, a mean accuracy of 0.93 (STD  =  0.12) was obtained on the test dataset. This study shows the potential of using HSI in colorectal cancer surgery for fast tissue classification, which could improve clinical outcome. Future research should be focused on imaging entire colon/rectum specimen and the translation of the technique to an intraoperative setting.
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http://dx.doi.org/10.1117/1.JBO.24.1.016002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985687PMC
January 2019

Prospective study on image-guided navigation surgery for pelvic malignancies.

J Surg Oncol 2019 Mar 24;119(4):510-517. Epub 2018 Dec 24.

Department of Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.

Background And Objectives: Surgery of advanced tumors and lymph nodes in the pelvis can be challenging due to the narrow pelvic space and vital surrounding structures. This study explores the application of a novel electromagnetic navigation system to guide pelvic surgery.

Methods: This was a prospective study on surgery for malignancies in the pelvis. Preoperatively obtained imaging was used to create a patient-specific three-dimensional (3D) roadmap. In the operating room, the 3D roadmap was registered to an intraoperative computed tomography scan. A tracked pointer was used during surgery for guidance. Primary endpoint was safety and feasibility, secondary endpoints were accuracy and usability.

Results: Twenty-eight colorectal, four liposarcomas, and one gynecological patient were included. There were no safety issues. Navigation was feasible in 31 patients. The mean target registration errors of 4.0 and 6.3 mm were achieved for straight and French position, respectively. In seven of seven patients with a locally advanced rectal tumor and in seven of eight patients with recurrences, negative margins were achieved. Thirty-three of 36 target lymph nodes were successfully removed. Surgeons using the system indicated faster localization of the tumor and improved decisiveness.

Conclusion: This novel surgical navigation system was safe and feasible during pelvic surgery and can facilitate its users.
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http://dx.doi.org/10.1002/jso.25351DOI Listing
March 2019

Treatment of Isolated Peritoneal Recurrences in Patients with Colorectal Peritoneal Metastases Previously Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2018 Jul 18;25(7):1992-2001. Epub 2018 Apr 18.

Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Colorectal peritoneal carcinomatosis (PC) is preferably treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Peritoneal recurrence of disease after treatment can occur without distant metastases, with a variety of treatment options.

Objective: This study aimed to evaluate the management of isolated peritoneal recurrence after primary CRS-HIPEC.

Methods: In two tertiary referral centers, all patients who underwent CRS-HIPEC for colorectal PC between 2004 and 2015 and who developed isolated peritoneal recurrences were retrospectively evaluated. Location, treatment of peritoneal recurrences, and curative or palliative treatment intent were reported, and univariable and multivariable Cox regression analysis and survival analyses were performed.

Results: Of 414 patients treated with CRS-HIPEC for colorectal PC, 106 patients (26%) developed isolated peritoneal recurrence. Forty-three patients (41%) were treated with curative intent and 63 (59%) were treated with palliative intent. Median overall survival (OS) in the patients treated with curative intent was 24.7 months (interquartile range [IQR] 12.1-61.7), compared with 7.6 months (IQR 2.5-15.9) in those treated with palliative intent (p < 0.001). In the patients treated with curative CRS (n = 17) and curative second CRS-HIPEC (n = 15), median OS was 51.7 months (IQR 14.4-NA) and 29.0 months (IQR 18.1-63.0), respectively (p = 0.620). The latter group had a significantly higher region count (median 1 vs. 3; p < 0.001). Postoperative complications and hospital stay did not significantly differ between first and second CRS-HIPEC.

Conclusion: After CRS-HIPEC for colorectal cancer, approximately one of four patients will develop isolated peritoneal recurrences. A substantial amount of these patients can be safely treated with curative intent yielding long-term survival.
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http://dx.doi.org/10.1245/s10434-018-6423-8DOI Listing
July 2018

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

N Engl J Med 2018 01;378(3):230-240

From the Departments of Gynecology (W.J.D., S.N.K.), Biometrics (K.S., H.T.), Surgical Oncology (A.G.J.A.), Pathology (K.K.V.V.), and Medical Oncology (S.N.K., G.S.S.) and the Division of Psychosocial Research and Epidemiology (J.M.K., N.K.A.), the Netherlands Cancer Institute, Amsterdam, the Center for Gynecologic Oncology Amsterdam, Amsterdam (W.J.D., S.N.K., J.V.), the Dutch Gynecologic Oncology Group (W.J.D., J.H.S.L., H.W.R.S., R.H.M.H., J.V., H.J.A., L.F.A.G.M., G.S.S.), the Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam (J.V.), the Department of Obstetrics and Gynecology, Sint Antonius Hospital, Nieuwegein (J.H.S.L.), the Department of Gynecologic Oncology, UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht (H.W.R.S.), the Departments of Gynecology and Obstetrics (R.H.M.H.) and Surgery (I.H.J.T.H.), Catharina Hospital, Eindhoven, the Dutch Peritoneal Oncology Group (I.H.J.T.H., A.G.J.A.), the Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen (H.J.A.), and the Department of Gynecologic Oncology, Radboud University Medical Center, Nijmegen (L.F.A.G.M.) - all in the Netherlands; and the Department of Surgery, Aarhus University Hospital, Aarhus, Denmark (V.J.V.).

Background: Treatment of newly diagnosed advanced-stage ovarian cancer typically involves cytoreductive surgery and systemic chemotherapy. We conducted a trial to investigate whether the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery would improve outcomes among patients who were receiving neoadjuvant chemotherapy for stage III epithelial ovarian cancer.

Methods: In a multicenter, open-label, phase 3 trial, we randomly assigned 245 patients who had at least stable disease after three cycles of carboplatin (area under the curve of 5 to 6 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area) to undergo interval cytoreductive surgery either with or without administration of HIPEC with cisplatin (100 mg per square meter). Randomization was performed at the time of surgery in cases in which surgery that would result in no visible disease (complete cytoreduction) or surgery after which one or more residual tumors measuring 10 mm or less in diameter remain (optimal cytoreduction) was deemed to be feasible. Three additional cycles of carboplatin and paclitaxel were administered postoperatively. The primary end point was recurrence-free survival. Overall survival and the side-effect profile were key secondary end points.

Results: In the intention-to-treat analysis, events of disease recurrence or death occurred in 110 of the 123 patients (89%) who underwent cytoreductive surgery without HIPEC (surgery group) and in 99 of the 122 patients (81%) who underwent cytoreductive surgery with HIPEC (surgery-plus-HIPEC group) (hazard ratio for disease recurrence or death, 0.66; 95% confidence interval [CI], 0.50 to 0.87; P=0.003). The median recurrence-free survival was 10.7 months in the surgery group and 14.2 months in the surgery-plus-HIPEC group. At a median follow-up of 4.7 years, 76 patients (62%) in the surgery group and 61 patients (50%) in the surgery-plus-HIPEC group had died (hazard ratio, 0.67; 95% CI, 0.48 to 0.94; P=0.02). The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group. The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups (25% in the surgery group and 27% in the surgery-plus-HIPEC group, P=0.76).

Conclusions: Among patients with stage III epithelial ovarian cancer, the addition of HIPEC to interval cytoreductive surgery resulted in longer recurrence-free survival and overall survival than surgery alone and did not result in higher rates of side effects. (Funded by the Dutch Cancer Society; ClinicalTrials.gov number, NCT00426257 ; EudraCT number, 2006-003466-34 .).
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http://dx.doi.org/10.1056/NEJMoa1708618DOI Listing
January 2018

Diffuse reflectance spectroscopy as a tool for real-time tissue assessment during colorectal cancer surgery.

J Biomed Opt 2017 Oct;22(10):1-6

Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Department of Surgery, Amsterdam, The Netherlands.

Colorectal surgery is the standard treatment for patients with colorectal cancer. To overcome two of the main challenges, the circumferential resection margin and postoperative complications, real-time tissue assessment could be of great benefit during surgery. In this ex vivo study, diffuse reflectance spectroscopy (DRS) was used to differentiate tumor tissue from healthy surrounding tissues in patients with colorectal neoplasia. DRS spectra were obtained from tumor tissue, healthy colon, or rectal wall and fat tissue, for every patient. Data were randomly divided into training (80%) and test (20%) sets. After spectral band selection, the spectra were classified using a quadratic classifier and a linear support vector machine. Of the 38 included patients, 36 had colorectal cancer and 2 had an adenoma. When the classifiers were applied to the test set, colorectal cancer could be discriminated from healthy tissue with an overall accuracy of 0.95 (±0.03). This study demonstrates the possibility to separate colorectal cancer from healthy surrounding tissue by applying DRS. High classification accuracies were obtained both in homogeneous and inhomogeneous tissues. This is a fundamental step toward the development of a tool for real-time in vivo tissue assessment during colorectal surgery.
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http://dx.doi.org/10.1117/1.JBO.22.10.106014DOI Listing
October 2017

Timing of Systemic Chemotherapy in Patients With Colorectal Peritoneal Carcinomatosis Treated With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Dis Colon Rectum 2017 May;60(5):477-487

1 Department of Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands 2 Department of Epidemiology and Biostatistics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands 3 Department of Radiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands 4 Department of Medical Oncology and Gastroenterology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

Background: Timing of systemic chemotherapy in patients with colorectal peritoneal carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is controversial. Preoperative systemic chemotherapy may offer benefits.

Objective: The purpose of this study was to evaluate the effect of timing of systemic chemotherapy on survival.

Design: This was a retrospective cohort study.

Settings: The study was conducted at a tertiary referral center.

Patients: Patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from January 2004 until June 2015 were included.

Main Outcome Measures: The influence of patient-related, tumor-related, and treatment-related factors on survival were investigated using Cox regression models. Main outcome was overall survival.

Results: A total of 280 consecutive patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. In group A, 78 patients (28%) were treated with preoperative or perioperative chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. In group B, 169 patients (60%) were intentionally treated with cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, and adjuvant chemotherapy. In group C, 33 patients (12%) had received their chemotherapy before peritoneal carcinomatosis was diagnosed. Median overall survival was 36.9 months (interquartile range, 20.6-79.7 mo) in group A, 43.1 months (interquartile range, 25.7-95.9 mo) in group B, and 34.0 months (interquartile range, 20.0-53.7 mo) in group C (p = 0.19). The extent of peritoneal carcinomatosis (region count of 3-5, HR = 1.58 (95% CI, 1.02-2.45), and 6-7, HR = 3.34 (95% CI, 1.66-6.72) vs 1-2 regions), a higher lymph node ratio (HR = 7.96 (95% CI, 2.16-29.31)), and cycles of systemic chemotherapy (0 cycles, HR = 2.52 (95% CI, 1.48-4.29)) and partial chemotherapy (HR = 2.15 (95% CI, 1.27-3.65) vs complete chemotherapy) were associated with poorer overall survival.

Limitations: Selection bias is present because of the retrospective design of this study.

Conclusions: Timing of systemic chemotherapy does not appear to have impact on survival in patients with colorectal peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
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http://dx.doi.org/10.1097/DCR.0000000000000774DOI Listing
May 2017

Survival of patients with colorectal peritoneal metastases is affected by treatment disparities among hospitals of diagnosis: A nationwide population-based study.

Eur J Cancer 2017 04 20;75:132-140. Epub 2017 Feb 20.

Department of Surgery, Catharina Hospital, PO Box 1350, 5602 ZA, Eindhoven, The Netherlands. Electronic address:

Background: In the Netherlands, surgery for peritoneal metastases of colorectal cancer (PMCRC) is centralised, whereas PMCRC is diagnosed in all hospitals. This study assessed whether hospital of diagnosis affects treatment selection and overall survival (OS).

Methods: Between 2005 and 2015, all patients with synchronous PMCRC without systemic metastases were selected from the Netherlands Cancer Registry. Treatment was classified as cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), systemic therapy or other/no treatment. Hospitals of diagnosis were classified as: (1) non-teaching or academic/teaching hospital and (2) HIPEC centre or referring hospital. Referring hospitals were further classified based on the frequency of CRS/HIPEC as high-, medium- or low-frequency hospital. Multivariable regression analyses were used to assess the independent influence of hospital categories on the likelihood of CRS/HIPEC and OS.

Results: A total of 2661 patients, diagnosed in 89 hospitals, were included. At individual hospital level, CRS/HIPEC and systemic therapy ranged from 0% to 50% and 6% to 67%, respectively. Hospital of diagnosis influenced the likelihood of CRS/HIPEC: 33% versus 13% for HIPEC centres versus referring hospitals (odds ratio (OR) 3.66 [2.40-5.58]) and 11% versus 17% for non-teaching hospitals versus academic/teaching hospitals (OR 0.60 [0.47-0.77]). Hospital of diagnosis affected median OS: 14.1 versus 9.6 months for HIPEC centres versus referring hospitals (hazard ratio (HR) 0.82 [0.67-0.99]) and 8.7 versus 11.5 months for non-teaching hospitals versus academic/teaching hospitals (HR 1.15 [1.06-1.26]). Compared with diagnosis in medium-frequency referring hospitals, median OS was increased in high-frequency referring hospitals (12.6 months, HR 0.82 [0.73-0.91]) and reduced in low-frequency referring hospitals (8.1 months, HR 1.12 [1.01-1.24]).

Conclusion: Treatment disparities among hospitals of diagnosis and their impact on survival indicate suboptimal treatment selection for PMCRC.
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http://dx.doi.org/10.1016/j.ejca.2016.12.034DOI Listing
April 2017

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BMC Cancer 2015 May 24;15:428. Epub 2015 May 24.

Department of surgery, Academic Medical Centre, University of Amsterdam, Post box 22660, 1105AZ, Amsterdam, The Netherlands.

Background: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay.

Methods/design: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA.

Discussion: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival.

Trial Registration Number: NCT02231086 (Clinicaltrials.gov).
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http://dx.doi.org/10.1186/s12885-015-1430-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492087PMC
May 2015

Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy.

World J Surg 2015 Feb;39(2):453-60

Department of Surgical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands,

Background: Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented.

Methods: The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP).

Results: Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p < 0.001), more resections (mean 3.8 vs. 3.4, p < 0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p < 0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p < 0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group.

Conclusions: This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity.
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http://dx.doi.org/10.1007/s00268-014-2801-yDOI Listing
February 2015

Synchronous colorectal carcinoma: a risk factor in colorectal cancer surgery.

Dis Colon Rectum 2014 Apr;57(4):460-6

1Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands 2Department of Surgery, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands 3Department of Surgery, Deventer Hospital, Deventer, the Netherlands.

Background: Synchronous colorectal carcinoma occurs in 1% to 8% of cases. There are little data on the impact of synchronous colorectal cancer on surgical treatment and short-term postoperative outcomes.

Objective: The purpose of this work was to evaluate clinical characteristics and treatment patterns of synchronous colorectal carcinoma and their influence on short-term postoperative outcomes in comparison with solitary colorectal carcinoma.

Design: This was a population-based observational study. Patient and tumor characteristics, treatment patterns, and postoperative outcomes are described for patients with a solitary and synchronous colorectal carcinoma separately. Multivariable logistic regression analysis was used to analyze the association between synchronous colorectal carcinoma and postoperative complications in comparison with a solitary colorectal carcinoma.

Settings: The study included in-hospital registration for the Dutch Surgical Colorectal Audit.

Patients: Patients were those with primary colorectal carcinoma from 2009 to 2011.

Main Outcome Measures: Severe postoperative complications, reinterventions, and 30-day mortality were measured.

Results: Of 25,413 patients with colorectal cancer, 884 (3.5%) had synchronous colorectal tumors. Patients with synchronous colorectal carcinoma were older and more often of male sex compared with patients with solitary colorectal carcinoma. In ≥ 35% of cases, an extended surgical procedure was conducted (n = 310). In multivariable logistic regression analysis, synchronous colorectal carcinoma was associated with a higher risk of severe postoperative complications (OR, 1.40; 95% CI, 1.20-1.63) and reinterventions (OR, 1.37; 95% CI, 1.14-1.65) compared with solitary colorectal carcinoma but not with higher 30-day mortality (OR, 1.34; 95% CI, 0.96-1.88).

Limitations: This study was limited by the data being self-reported. Case-mix adjustment was limited to information available in the data set, and no long-term outcome data were available.

Conclusions: Synchronous colorectal carcinomas are prevalent in 3.5% of patients and require a different treatment strategy in comparison with solitary colorectal carcinoma. Postoperative outcomes are unfavorable, most likely because of extensive surgery.
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http://dx.doi.org/10.1097/DCR.0000000000000068DOI Listing
April 2014

Morbidity associated with colostomy reversal after cytoreductive surgery and HIPEC.

Ann Surg Oncol 2014 Mar 18;21(3):883-90. Epub 2013 Nov 18.

Department of Surgical Oncology, VU University Medical Center, Amsterdam, The Netherlands,

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the survival in selected colorectal cancer patients with peritoneal metastases. In these patients, the risk of a low anastomosis is sometimes diminished through the creation of a colostomy. Currently, the morbidity and mortality associated with the reversal of the colostomy in this population is unknown.

Methods: Our study involved two prospectively collected databases including all patients who underwent CRS-HIPEC. We identified all consecutive patients who had a colostomy and requested a reversal. The associations between four clinical and ten treatment-related factors with the outcome of the reversal procedure were determined by univariate analysis.

Results: 21 of 336 patients (6.3 %) with a stoma with a mean age of 50.8 (standard deviation 10.2) years underwent a reversal procedure. One patient was classified as American Society of Anesthesiologists (ASA) grade III, 6 as ASA grade II, and the remaining as ASA grade I. Median time elapsed between HIPEC and reversal was 394 days (range 133-1194 days). No life-threatening complications or mortality were observed after reversal. The reversal-related morbidity was 67 %. Infectious complications were observed in 7 patients (33 %). Infectious complications after HIPEC were negatively correlated with the ultimate restoration of bowel continuity (P = 0.05). Bowel continuity was successfully restored in 71 % of the patients.

Conclusions: Although the restoration of bowel continuity after CRS-HIPEC was successful in most patients, a relatively high complication rate was observed. Patients with infectious complications after HIPEC have a diminished chance of successful restoration of bowel continuity.
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http://dx.doi.org/10.1245/s10434-013-3370-2DOI Listing
March 2014

Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol.

Ann Surg Oncol 2013 Dec 30;20(13):4224-30. Epub 2013 Jul 30.

Department of Surgical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands,

Purpose: This nationwide study evaluated results of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis of colorectal origin in the Netherlands following a national protocol.

Methods: In a multi-institutional study prospective databases of patients with peritoneal carcinomatosis (PC) from colorectal cancer and pseudomyxoma peritonei (PMP) treated according to the Dutch HIPEC protocol, a uniform approach for the CRS and HIPEC treatment, were reviewed. Primary end point was overall survival and secondary end points were surgical outcome and progression-free survival.

Results: Nine-hundred sixty patients were included; 660 patients (69 %) were affected by PC of colorectal carcinoma and the remaining suffered from PMP (31 %). In 767 procedures (80 %), macroscopic complete cytoreduction was achieved. Three-hundred and thirty one patients had grade III-V complications (34 %). Thirty-two patients died perioperatively (3 %). Median length of hospital stay was 16 days (range 0-166 days). Median follow-up period was 41 months (95 % confidence interval (CI), 36-46 months). Median progression-free survival was 15 months (95 % CI 13-17 months) for CRC patients and 53 months (95 % CI 40-66 months) for PMP patients. Overall median survival was 33 (95 % CI 28-38 months) months for CRC patients and 130 months (95 % CI 98-162 months) for PMP patients. Three- and five-year survival rates were 46 and 31 % respectively in case of CRC patients and 77 and 65 % respectively in case of PMP patients.

Conclusions: The results underline the safety and efficacy of cytoreduction and HIPEC for PC from CRC and PMP. It is assumed the uniform Dutch HIPEC protocol was beneficial.
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http://dx.doi.org/10.1245/s10434-013-3145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827901PMC
December 2013

Polymorphonuclear leukocytes increase the adhesion of circulating tumor cells to microvascular endothelium.

Anticancer Res 2007 Jan-Feb;27(1A):17-22

Department of Surgery, Erasmus MC Rotterdam, The Netherlands.

Background: Reactive oxygen species (ROS) released from activated polymorphonuclear leukocytes (PMN) during surgery may play a crucial role in the enhanced distant tumor recurrence after surgical trauma.

Materials And Methods: The effect of PMN on the adhesion of the human colon carcinoma cells HT29, Caco2 and the pancreatic carcinoma cells PanC1 and BxPC3 to microvascular endothelium (MEC) was studied in a reproducible human in vitro model.

Results: Pre-incubation of MEC with tissue plasminogen activator (TPA)-activated PMN resulted in more than 200% increase of tumor cell adhesion to MEC compared to control (p < 0.01). Exposure of MEC to TPA or non-activated PMN did not significantly affect adhesion. Addition of the antioxidant enzymes superoxide dismutase or catalase significantly decreased tumor cell adhesion to MEC exposed to PMN.

Conclusion: These results demonstrate that activated PMN promote tumor cell adhesion to the microvascular wall by production of ROS. This indicates that in tackling the ROS production, preventing tumor recurrence at distant sites, might be feasible.
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March 2007
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