Whole-body MRI with diffusion-weighted imaging as an adjunct to18 F-fluorodeoxyglucose positron emission tomography and CT in patients with suspected recurrent colorectal cancer.

AIM: The aim was to explore how findings of whole-body MRI including diffusion-weighted imaging (DW-MRI) compared to the routine diagnostic workup with CT and/or 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with suspected recurrent colorectal cancer (CRC). METHOD: This was an exploratory retrospective analysis of 55 patients with a clinical suspicion of recurrent CRC who underwent DW-MRI following CT and/or FDG-PET/CT. Two readers in consensus interpreted all clinical imaging reports and converted each described lesion into a confidence score (1 = definitely benign to 5 = definitely malignant). DW-MRI findings were compared to the most recent previous CT or PET/CT. Any discrepant or additional DW-MRI findings were documented and compared with histology and/or clinical follow-up (if available). RESULTS: Whole-body MRI including diffusion-weighted imaging (DW-MRI) resulted in discrepant/additional findings in 26/55 (47%) cases; 23/37 (62%) compared to previous CT and 3/18 (17%) compared to previous PET/CT. These included 10 cases where DW-MRI converted previously inconclusive CT (n = 8) or PET/CT (n = 2) findings into a conclusive diagnosis, one where it contradicted a previous CT diagnosis of recurrence, five where DW-MRI diagnosed recurrent disease not previously reported on CT and 10 cases where DW-MRI detected additional lesions compared to CT (n = 9) or PET/CT (n = 1). Eighty-eight per cent of cases with discrepant/additional findings concerned patients with recurrent/metachronous peritoneal metastases. In total, DW-MRI resulted in 42 discrepant/additional lesions; the DW-MRI diagnosis was correct in 76% of these lesions and incorrect (false positive) in 7%. In the remaining 17%, no standard of reference was available. CONCLUSIONS: This explorative study suggests that DW-MRI may be of added value to patients with a clinical suspicion for recurrent CRC, in particular to identify patients with peritoneal metastases. DW-MRI mainly has potential as a 'problem-solver' in patients with inconclusive or negative findings on previous imaging (in particular CT) and to detect additional disease sites in patients already diagnosed with recurrent disease.

Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer (OVHIPEC-1): final survival analysis of a randomised, controlled, phase 3 trial.

BACKGROUND: The OVHIPEC-1 trial previously showed that the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery resulted in improved progression-free and overall survival compared with cytoreductive surgery alone at 4·7 years of follow-up in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. We report the final survival outcomes after 10 years of follow-up. METHODS: In this open-label, randomised, controlled, phase 3 trial, patients with primary epithelial stage III ovarian cancer were recruited at eight HIPEC centres in the Netherlands and Belgium. Patients were eligible if they were aged 18-76 years, had not progressed during at least three cycles of neoadjuvant carboplatin plus paclitaxel, had a WHO performance status score of 0-2, normal blood counts, and adequate renal function. Patients were randomly assigned (1:1) to undergo interval cytoreductive surgery without HIPEC (surgery group) or with HIPEC (100 mg/m2 cisplatin; surgery-plus-HIPEC group). Randomisation was done centrally by minimisation with a masked web-based allocation procedure at the time of surgery when residual disease smaller than 10 mm diameter was anticipated, and was stratified by institution, previous suboptimal cytoreductive surgery, and number of abdominal regions involved. The primary endpoint was progression-free survival and a secondary endpoint was overall survival, analysed in the intention-to-treat population (ie, all randomly assigned patients). This study is registered with ClinicalTrials.gov, NCT00426257, and is closed. FINDINGS: Between April 1, 2007, and April 30, 2016, 245 patients were enrolled and followed up for a median of 10·1 years (95% CI 8·4-12·9) in the surgery group (n=123) and 10·4 years (95% CI 9·5-13·3) in the surgery-plus-HIPEC group (n=122). Recurrence, progression, or death occurred in 114 (93%) patients in the surgery group (median progression-free survival 10·7 months [95% CI 9·6-12·0]) and 109 (89%) patients in the surgery-plus-HIPEC group (14·3 months [12·0-18·5]; hazard ratio [HR] 0·63 [95% CI 0·48-0·83], stratified log-rank p=0·0008). Death occurred in 108 (88%) patients in the surgery group (median overall survival 33·3 months [95% CI 29·0-39·1]) and 100 (82%) patients in the surgery-plus-HIPEC group (44·9 months [95% CI 38·6-55·1]; HR 0·70 [95% CI 0·53-0·92], stratified log-rank p=0·011). INTERPRETATION: These updated survival results confirm the long-term survival benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. FUNDING: Dutch Cancer Foundation (KWF Kankerbestrijding).

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Incidence, treatment and survival of malignant pleural and peritoneal mesothelioma: a population-based study.

INTRODUCTION: Malignant mesothelioma (MM) is an aggressive cancer that primarily arises from the pleura (MPM) or peritoneum (MPeM), mostly due to asbestos exposure. This study reviewed the Dutch population-based incidence, treatment and survival since the national ban on asbestos in 1993. MATERIALS AND METHODS: Patients with MPM or MPeM diagnosed from 1993 to 2018 were selected from the Dutch cancer registry. Annual percentage change (APC) was calculated for (age-specific and sex-specific) revised European standardised incidence rates (RESR). Treatment pattern and Kaplan-Meier overall survival analyses were performed. RESULTS: In total, 12 168 patients were included in the study. For male patients younger than 80 years, the MM incidence significantly decreased in the last decade (APC ranging between -9.4% and -1.8%, p<0.01). Among both male and female patients aged over 80 years, the incidence significantly increased during the entire study period (APC 3.3% and 4.6%, respectively, p<0.01). From 2003 onwards, the use of systemic chemotherapy increased especially for MPM (from 9.3% to 39.4%). Overall, 62.2% of patients received no antitumour treatment. The most common reasons for not undergoing antitumour treatment were patient preference (42%) and performance status (25.6%). The median overall survival improved from 7.3 (1993-2003) to 8.9 (2004-2011) and 9.3 months from 2012 to 2018 (p<0.001). CONCLUSION: The peak of MM incidence was reached around 2010 in the Netherlands, and currently the incidence is declining in most age groups. The use of systemic chemotherapy increased from 2003, which likely resulted in improved overall survival over time. The majority of patients do not receive treatment though and prognosis is still poor.

Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer.

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 .).

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

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.

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

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.

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

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.

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).

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.

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

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.

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)

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 .

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

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.

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

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.

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

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).

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

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.

Morbidity associated with colostomy reversal after cytoreductive surgery and HIPEC.

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.

Imaging in the era of risk-adapted treatment in colon cancer.

The treatment landscape for patients with colon cancer is continuously evolving. Risk-adapted treatment strategies, including neoadjuvant chemotherapy and immunotherapy, are slowly finding their way into clinical practice and guidelines. Radiologists are pivotal in guiding clinicians toward the most optimal treatment for each colon cancer patient. This review provides an overview of recent and upcoming advances in the diagnostic management of colon cancer and the radiologist's role in the multidisciplinary approach to treating colon cancer.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

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

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.