Impact of cumulative complications on 1-year treatment-related healthcare costs in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of all minor and major complications on treatment-related healthcare costs in patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of colorectal peritoneal metastases (PMs). METHOD: Patients with histologically proven colorectal PMs who underwent CRS + HIPEC from March 2006 to October 2019 in a tertiary referral centre were retrospectively identified from a prospectively maintained database. Patients were divided into six subgroups according to the severity of the complications, which were scored using the comprehensive complication index (CCI) (CCI 0-9.9, CCI 10-19.9, CCI 20-29.9, CCI 30-39.9, CCI 40-49.9, and CCI 50 or higher). Treatment-related healthcare costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the chi-squared test and Kruskal-Wallis H test. RESULTS: A total of 142 patients were included (CCI 0-9.9, 53 patients; CCI 10-19.9, 0 patients; CCI 20-29.9, 45 patients; CCI 30-39.9, 14 patients; CCI 40-49, 9 patients; and CCI 50 or higher, 21 patients). Median (interquartile range) treatment-related healthcare costs increased significantly and exponentially for the CCI 30-39, CCI 40-49, and CCI 50 or higher groups (€48 993 (€44 262-€84 805); €57 167 (€43 047-€67 591); and €82 219 (€55 487-€145 314) respectively) compared with those for the CCI 0-9.9 and CCI 20-29.9 groups (€33 856 (€24 433-€40 779) and €40 621 (€31 501-€58 761) respectively, P < 0.010). CONCLUSION: Treatment-related healthcare costs increase exponentially as more complications develop among patients who undergo CRS + HIPEC for the treatment of colorectal PMs. Anastomotic leakages after CRS + HIPEC lead to an increase of 295 per cent of treatment-related healthcare costs.

Systematic Review of Factors Affecting Quality of Life After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Previous studies have shown that, overall, quality of life (QoL) decreases within the first 3-6 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC), returning to baseline levels by 6-12 months. This systematic review aims to evaluate the factors affecting QoL after CRS + HIPEC within 12 months of surgery. METHODS: Electronic databases were investigated searching for articles reporting QoL with validated questionnaires up to September 2019. Risk of bias was assessed with the methodological index for non-randomized studies tool. The primary outcomes were short-term (< 6 months after surgery) and medium-term (6-12 months after surgery) determinants of QoL after CRS + HIPEC. Secondary outcomes were QoL and reported symptoms over time. RESULTS: We included 14 studies that used 12 different questionnaires. The reported data were collected prospectively or retrospectively for 1556 patients (dropout < 50% in four studies). Overall, studies showed diminished QoL within 3 months after surgery and a recovery to baseline or greater by 12 months. QoL was negatively influenced by higher age, female sex, prolonged operation time, extensive disease, residual disease, adjuvant chemotherapy, complications, stoma placement, and recurrent disease. QoL results were comparable between studies, with dropout rates above and below 50%. CONCLUSIONS: QoL returns to baseline levels within 12 months after CRS + HIPEC provided the disease does not recur, and this recovery process is influenced by several factors.

Delta peritoneal cancer index (ΔPCI): A new dynamic prognostic parameter for survival in patients with colorectal peritoneal metastases.

BACKGROUND: The peritoneal cancer index (PCI) calculated during exploratory laparotomy is a strong prognostic factor for overall survival (OS) in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Progression of the PCI between diagnostic laparoscopy (DLS) and potential CRS + HIPEC (ΔPCI) might be a more dynamic prognostic factor for OS after CRS + HIPEC. MATERIALS AND METHODS: Between 2012 and 2018, all colorectal PM patients who underwent an exploratory laparotomy for potential CRS + HIPEC after DLS were retrospectively identified from a prospectively maintained database. Patients were divided into stable disease (ΔPCI 0-3), mild progression (ΔPCI 4-9), or severe progression (ΔPCI ≥10). Kaplan-Meier analysis and a multivariate Cox regression were performed. RESULTS: Eighty-four patients (ΔPCI 0-3, n = 35; ΔPCI 4-9, n = 34; and ΔPCI ≥10, n = 15) were analysed. Median OS after CRS + HIPEC was significantly decreased in patients with a ΔPCI of 4-9 (35.1 [95% CI 25.5-44.6]) or ΔPCI ≥10 (24.1 [95% CI 11.7-36.5]) compared to patients with a ΔPCI of 0-3 (47.9 [95% CI 40.0-55.7], p = 0.004). In multivariate regression analysis, ΔPCI remained an independent risk factor for OS: ΔPCI 4-9 HR 3.1 (95% CI 1.4-7.2, p = 0.007) and ΔPCI ≥10 HR 4.4 (95% CI 1.5-13.1, p = 0.007). CONCLUSION: A high ΔPCI is an independent dynamic prognostic factor for OS and might reflect a more aggressive tumour biology in patients with colorectal PM. HIPEC surgeons should be aware of a high-ΔPCI-associated diminished prognosis and should reconsider CRS + HIPEC when confronted with a ΔPCI ≥10.

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 .

Impact of Synchronous Versus Metachronous Onset of Colorectal Peritoneal Metastases on Survival Outcomes After Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Multicenter, Retrospective, Observational Study.

BACKGROUND: Careful selection of patients with colorectal peritoneal metastases (PM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is crucial. It remains unknown whether the time of onset of colorectal PM (synchronous vs metachronous) influences surgical morbidity and survival outcomes after CRS with HIPEC. METHODS: Patients with histologically proven colorectal PM who underwent CRS with HIPEC between February 2006 and December 2017 in two Dutch tertiary referral hospitals were retrospectively included from a prospectively maintained database. The onset of colorectal PM was classified as synchronous (PM diagnosed at the initiational presentation with colorectal cancer) or metachronous (PM diagnosed after initial curative colorectal resection). Major postoperative complications (Clavien-Dindo grade ≥ 3), overall survival (OS), and disease-free survival (DFS) were compared between patients with synchronous colorectal PM and those with metachronous colorectal PM using Kaplan-Meier analyses, proportional hazard analyses, and a multivariate Cox regression analysis. RESULTS: The study enrolled 433 patients, of whom 231 (53%) had synchronous colorectal PM and 202 (47%) had metachronous colorectal PM. The major postoperative complication rate and median OS were similar between the patients with synchronous colorectal PM and those with metachronous colorectal PM (26.8% vs 29.7%; p = 0.693 and 34 vs 33 months, respectively; p = 0.819). The median DFS was significantly decreased for the patients with metachronous colorectal PM and those with synchronous colorectal PM (11 vs 15 months; adjusted hazard ratio, 1.63; 95% confidence interval, 1.18-2.26). CONCLUSIONS: Metachronous onset of colorectal PM is associated with early recurrence after CRS with HIPEC compared with synchronous colorectal PM, without a difference in OS or major postoperative complications. Time to onset of colorectal PM should be taken into consideration to optimize patient selection for this major procedure.

Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Incidence of, and baseline characteristics associated with delirium in patients after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), were subject of investigation. METHODS: The study was conducted among a consecutive series of prospectively included patients who underwent CRS-HIPEC at the University Medical Center Groningen, Groningen, the Netherlands, between February 2006 and January 2015. A chart-based instrument for delirium during hospitalization was used to identify patients with symptoms of delirium who were not diagnosed by a psychiatrist during admission. Uni- and multivariate logistic regression analyses were performed. RESULTS: Data of 136 patients were included in the analysis. Median age was 60 years (range: 18-76) and 50 (37%) patients were male. During hospitalization, 38 (28%) patients were diagnosed with delirium. Factors that differed significantly between the patients with and without delirium by univariate analysis were included in multivariate analysis. Multivariate analysis showed that after adjustment for age and complications other than delirium, having three or more organs resected and the CRP serum levels were independent predictors for delirium (OR: 3.97; 95% 1.24-12.76; OR: 1.01; 95% 1-1.01, respectively). CONCLUSIONS: This report shows an incidence of 28% of delirium, occurring after CRS-HIPEC and suggests a role for systemic inflammation in the development of postoperative delirium.

Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study.

BACKGROUND: Optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of peritoneal carcinomatosis of colorectal origin. At present, surgeons depend on visual inspection and palpation for tumour detection. Improved detection of tumour tissue using molecular fluorescence-guided surgery could not only help attain a complete cytoreduction of metastatic lesions, but might also prevent overtreatment by avoiding resection of benign lesions. METHODS: For this non-randomised, single-centre feasibility study, we enrolled patients with colorectal peritoneal metastases scheduled for cytoreductive surgery and HIPEC. 2 days before surgery, 4·5 mg of the near-infrared fluorescent tracer bevacizumab-IRDye800CW was administered intravenously. The primary objectives were to determine the safety and feasibility of molecular fluorescence-guided surgery using bevacizumab-IRDye800CW. Molecular fluorescence-guided surgery was deemed safe if no allergic or anaphylactic reactions were recorded and no serious adverse events were attributed to bevacizumab-IRDye800CW. The technique was deemed feasible if bevacizumab-IRDye800CW enabled detection of fluorescence signals intraoperatively. Secondary objectives were correlation of fluorescence with histopathology by back-table imaging of the fresh surgical specimen and semi-quantitative ex-vivo analyses of formalin-fixed paraffin embedded (FFPE) tissue on all peritoneal lesions. Additionally, VEGF-α staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632. FINDINGS: Between July 3, 2014, and March 2, 2015, seven patients were enrolled in the study. One patient developed an abdominal sepsis 5 days postoperatively and another died from an asystole 4 days postoperatively, most probably due to a cardiovascular thromboembolic event. However, both serious adverse events were attributed to the surgical cytoreductive surgery and HIPEC procedure. No serious adverse events related to bevacizumab-IRDye800CW occurred in any of the patients. Intraoperatively, fluorescence was seen in all patients. In two patients, additional tumour tissue was detected by molecular fluorescence-guided surgery that was initially missed by the surgeons. During back-table imaging of fresh surgical specimens, a total of 80 areas were imaged, marked, and analysed. All of the 29 non-fluorescent areas were found to contain only benign tissue, whereas tumour tissue was detected in 27 of 51 fluorescent areas (53%). Ex-vivo semi-quantification of 79 FFPE peritoneal lesions showed a tumour-to-normal ratio of 6·92 (SD 2·47). INTERPRETATION: Molecular fluorescence-guided surgery using the near-infrared fluorescent tracer bevacizumab-IRDye800CW is safe and feasible. This technique might be of added value for the treatment of patients with colorectal peritoneal metastases through improved patient selection and optimisation of cytoreductive surgery. A subsequent multicentre phase 2 trial is needed to make a definitive assessment of the diagnostic accuracy and the effect on clinical decision making of molecular fluorescence-guided surgery. FUNDING: FP-7 Framework Programme BetaCure and SurgVision BV.

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.

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.

Quality of life after hyperthermic isolated limb perfusion for locally advanced extremity soft tissue sarcoma.

BACKGROUND: Quality of life (QoL) and posttraumatic stress symptoms (PTSS) were studied in patients with soft tissue sarcoma (STS) of the extremities treated with isolated limb perfusion and delayed resection, with or without adjuvant irradiation. METHODS: Forty-one patients received a questionnaire that included the RAND-36 and Impact of Event Scale. RESULTS: Thirty-nine STS survivors (16 [41%] male and 23 [59%] female; median age, 59 years; range, 15-78 years) participated in the questionnaire survey (response rate, 95%). The median age at perfusion was 49 years (range, 14-72 years). No significant differences were found in mean scores between STS survivors and the reference group with the exception of a worse physical functioning. Patients with amputations showed significantly worse physical and social functioning and more role limitations than patients whose limbs were saved. Eleven patients (28%) had a PTSS score of 0, and eight patients (20.5%) had a score>or=26, which suggested the need for psychological counseling. None of these eight patients had lost a limb. Patients who indicated that the choice of treatment was made by the surgeon rather than collaboratively showed significantly decreased social functioning, more role limitations, and intrusion. Greater treatment satisfaction was significantly related to better social functioning, more vitality, better general health perception, less intrusion, avoidance, and total Impact of Event Scale scores. CONCLUSIONS: Even though STS survivors' QoL was different from that of a reference group only in physical functioning, one fifth of the patients had PTSS. An amputation, the physician's decision rather than the patient's decision for the perfusion treatment and a low satisfaction with the performed treatment negatively influenced QoL.

Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma: the value of adjuvant radiotherapy.

BACKGROUND: The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan followed by limb-saving surgery. METHODS: From 1991 to 2003, 73 patients (median age, 54 years; range, 14-80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test. RESULTS: After residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT- group). The median follow-up was 28 months (range, 2-159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT- group (P<.0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups (P=.0003). In the EBRT- group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections (P=.0475). CONCLUSIONS: Adjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection.