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serum cystatin C

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neutrophil gelatinase-associated lipocalin

urine

Chao-Yu Chen, MD

Feng-Chi Lung, Bachelor

Hung-Yu Chang, MD

Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) is an emerging surgical procedure for peritoneal carcinomatosis. Despite the survival benefits from HIPEC, complications have been reported with major morbidity and mortality. Acute kidney injury (AKI) is one of the major complications. To date, there is no adequate biomarker to predict the risk of AKI after HIPEC and monitor the renal prognosis after HIPEC-related AKI.

Aims:

1. Establish a HIPEC cohort database, including retrospective data and prospective database
2. Identify the incidence of AKI after HIPEC and the severity
3. Identify the biomarker to predictive HIPEC-related AKI and monitor renal prognosis. Understand the risk factors for AKI post- HIPEC helps improve pre-operative patient selection and optimization, facilitate tailoring of chemotherapy, and foster closer peri-operative monitoring and fluid management in at-risk patients.

Methods:

1. Patients with the peritoneal carcinomatosis, planning to receive HIPEC and agree to participate the study will be recruited.
2. Retrospective analyze the renal prognosis of patients with HIPEC procedure and identify the clinical and biochemistry risk factors of HIPEC-related AKI
3. Prospective collect the information of patients who are enrolled into this study. The information includes clinical information, biochemistry, electrolyte, and novel biomarkers of body fluids (blood, and urine). The samples of body fluids will be collected on pre-operative day, post-operative 2h, 24h, 48h, 72h and day 7. Patients with or without post-HIPEC AKI will be analyzed.

Hypothesis:

1. Peri-operative dehydration and cisplatin-based regimen are the major risk factors to cause AKI.
2. The novel biomarker, high peri-operative urine NGAL and serum cystatin C, β2 Microglobulin are the predictive markers of HIPEC- related AKI.

Introduction Peritoneal carcinomatosis (PC) is a serious oncological condition in patients with metastatic malignancy, for which cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has become the treatment of choice. In this procedure, chemotherapeutic drugs are introduced intraoperatively into the peritoneal cavity at temperature 41-43 °C. The abdominal cavity is perfused for about 60-90 minutes, thereby exposing potential microscopic residual cancer cells directly to the synergistic effects of hyperthermia (Sugarbaker 2016). In highly selected patients with colorectal cancer, CRS/HIPEC has shown benefits in disease-free and overall survival compared to systemic chemotherapy alone, with a 5-year survival rate of up to 45% for patients with no residual tumor after completing CRS. Furthermore, in patients with PMP receiving CRS/HIPEC, the survival rate beyond 10 years has been reported to reach 63% (Yan, Stuart et al. 2006, Verwaal, Bruin et al. 2008).

CRS/HIPEC is an aggressive treatment modality, often associated with high-grade complications. Recent publications have reported morbidity and mortality rates of 2.5-25% and 1.5-11%, respectively, with renal toxicity and bone marrow failure accounting for most causes of systemic toxicity (Ihemelandu, McQuellon et al. 2013, Wang, Chen et al. 2017). Acute kidney injury (AKI) is a serious morbidity that is associated with a greater duration of hospitalization, higher risk of mortality and increased risk of progressive chronic kidney disease. It has been described after the administration of HIPEC with cisplatin, with the quoted incidence of major renal toxicity ranging from 1.3-5.9% (Sin, Chia et al. 2017).

Renal toxicity of HIPEC Chemotherapy effect Cisplatin, a platinum-based anticancer agent, exerts its cytotoxic effect by binding and cross-linking DNA. It has been utilized as a cornerstone in many HIPEC protocols at variable doses for the treatment of tumors with PC, including primary peritoneal neoplasms, sarcomas, and gynecological tumors. Cisplatin-induced nephrotoxicity is a complex process involving acute cytotoxicity to tubular epithelium, followed by inflammatory cell infiltration and fibroproliferative changes. A recent pharmacokinetic study of this regimen yielded a cisplatin perfusate-to-blood area under the curve ratio of 6.28. These data indicate the absorption of cisplatin into the circulation during HIPEC, hence systemic complications cannot be excluded. Western literatures reported that 4-6% incidence of renal toxicity among patients who underwent HIPEC using cisplatin at variable doses and combinations (Hakeam, Breakiet et al. 2014). However, higher incidence of renal toxicity was reported by Singapore. Tan et al reported that among the 47 patients, 19 (40.4%) experienced post-operative AKI, of which 5 (8.5%) developed grade 3 and 4 impairment. Two (4.3%) required long-term dialysis.

In addition, mitomycin and doxorubicin which are also often used as HIPEC regimens, are also known nephrotoxins (Hakeam, Breakiet et al. 2014).

Comorbidity effect Preexisting kidney damage, hypomagnesemia and concomitant use of other nephrotoxic agents may potentiate the development of renal impairment. Other factors associated with nephrotoxicity were possible lower intraoperative urine output, and diabetes mellius (Yan, Stuart et al. 2006, Hakeam, Breakiet et al. 2014).

Biomarker of renal toxicity The traditional diagnosis of AKI involves measurements of surrogate markers of the reduced glomerular filtration rate (GFR), such as a rise in serum creatinine levels and/or a reduction in urine output. However, measurement of serum creatinine levels has limitation as a screening test in the early stages of AKI (Schiffl and Lang 2012). The emergence of numerous renal tubular damage-specific biomarkers offers an opportunity to diagnose AKI at an early time point, to facilitate differential diagnosis of structural and functional AKI, and to predict the outcome of established AKI. The reported potential biomarkers are cystatin C and NGAL (neutrophil gelatinase-associated lipocalin).

Cystatin C Serum cystatin C concentration has been described in numerous studies as being superior to serum creatinine for assessment of glomerular filtration rate. Adding serum cystatin C to the combi¬nation of serum creatinine and albuminuria improved the predictive accuracy of a model of all-cause mortal¬ity and ESRD. Elevated serum levels of cystatin C are also associated with renal and cardiovascular complica¬tions.

NGAL Serum and urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) are elevated in several renal pathologies, including chronic glomerular disease, autosomal dominant polycystic kidney disease, and AKI. Elevated plasma NGAL was also suggested to be an excellent biomarker of com-plications associated with kidney disease, such as cardiovascular disease, and to be associated with progression as well as inhibition of tumor growth.

Beta-2 microglobulin β2 Microglobulin is a non-glycosylated protein. In the system, it possesses the negative charge. β2 Microglobulin is a component of MHC class 1 molecules, which are present on almost all cells of the body except red blood cells. β2 Microglobulin is generally required for the transport of MHC class I heavy chains from the endoplasmic reticulum to the cell surface. β2 Microglobulin is filtered by the glomerulus, absorbed and catabolised by the proximal tubules. Clinically the appearance of significant amount of this protein in urine is one of the earliest sign of almost all renal diseases. Serum creatinine is affected by factors other than GFR, in particular muscle mass and meat intake. β2 Microglobulin is released at constant rate in normal subjects, readily filters through the glomerular capillary wall, over 99.9% being reabsorbed and catabolised in proximal tubules with virtually no return of the filtered protein to the circulation. β2 Microglobulin is therefore theoretically a highly suitable biomarker of renal dysfunction.

Preliminary findings of HIPEC in Chang-Gung Memorial Hospital at Chiayi In the report of our preliminary data, the grade 3 complications were 30.7% in the very early cases and 12.4% after establishing multi-disciplinary teamwork (MDT) (Wang, Chen et al. 2017). We noted a trend of AKI in patients who underwent HIPEC with cisplatin. Permanent kidney injury was noted in two patients and transient AKI was noted in three cases in this database (2015/4-2016/12). Further two patients suffered from grade 3-4 AKI was also noted in 2017 even under MDT care.

Aims Previous studies mostly discuss the clinical risk factors of renal toxicity. Literature of biomarker related to HIPEC-related AKI is sparse. Herein, firstly, we aim to establish a HIPEC cohort database and retrospectively study the patients suffered from HIPEC-related AKI and identify the clinical risk factors and the renal prognosis. Furthermore, we will recruit blood, and urine samples to identify the novel biomarker to predictive HIPEC-related AKI and monitor renal prognosis. This can help to identify the risk factors for AKI and improve pre-operative patient's selection, facilitate tailoring of chemotherapy, and foster closer peri-operative monitoring and fluid management in high-risk patients.

Hypothesis

1. After retrospective chart review, peri-operative dehydration during operation (massive bleeding, prolong surgery with hyperthermia, etc) after HIPEC and cisplatin-based regimens are the major risk factor to cause AKI.
2. The novel biomarker, higher pre-operative urine NGAL and serum cystatin C, β2 Microglobulin are the predictive markers of patients who will have the peri-operative dehydration and correlate with HIPEC -related AKI.

Aim 1. To establish a HIPEC cohort database and retrospectively study the patients suffered from HIPEC-related AKI and identify the clinical risk factors and the renal prognosis.

Aim 2. To identify the novel biomarker (urine NGAL and serum cystatin C) to predictive HIPEC-related AKI and monitor renal prognosis.

Study design:

Aim 1. A single institution (Chang Gung Memorial Hospital at Chiayi), retrospective study Aim 2. Prospective cohort study to validate Aim 1. Clinical data, blood and urine samples should be collected.

Number of patients:

Aim 1. Chart review of patients who receiving HIPEC procedure from 2015/4-2018/12. The estimated case numbers are 180 cases. (100 cases of 2015/4-2017/9 plus estimated 80 cases from 2017/10-2017/12) Aim 2. Prospective collection of clinical data of 150 patients (estimated 50-60 cases /year).

Collect data:

Patient age, gender, cancer type, disease status (primary or recurrent), grade of differentiation, histology type, tumor burden (peritoneal carcinomatosis index), date of diagnosis/recurrence, site/pattern of recurrence, performance states, date of operation date, HIPEC parameters (chemotherapy regimens, perfusate, cytoreduction time, duration, and temperatures), peri-operative fluid status, pre-operative imaging date and types (CT or MRI, with or without contrast which is related to renal function), and date of death or lost to follow-up.

Routinely blood data are collected (CBC/DC, serum creatinine, BUN, liver function test, albumin, electrolyte, sugar, osmolarity...) on pre-operative, post-HIPEC 2hr, post-HIPEC 24 hours, 48 hours, 72 hours, day 7, and day 30.

Samples collection:

Blood and urine samples were evaluated using standard laboratory methods. The serum-cystatin C concentration and urine-NGAL in non-AKI and AKI groups are measured pre-operative day, post-operative 2h, 24h, 48h, 72h and day 7.

Statistic analysis:

The data will be analyzed by the SPSS 17·0 statistical package. Chi-square test and t-test for single variate analysis will be used to evaluate the association between covariates. Survival curves (cancer-specific survival \[CSS\] and recurrence-free survival \[RFS\]) will be generated using the Kaplan-Meier method. Multivariate analysis by cox stepwise forward regression will be used. Generalized estimating equation (GEE) will be used for those repeated measured data. Their hazard ratios (HR) and 95% confidence intervals (CI) will be calculated. All tests will be two-sided, and p values of \< 0·05 are considered statistically significant.

Blood and urine samples were evaluated using standard laboratory methods. The serum-cystatin C concentration and urine-NGAL in non-AKI and AKI groups are measured pre-operative day, post-operative 2h, 24h, 48h, 72h and day 7.

Risk of Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy

The data entry personnel will enter de-identified data of the patients as per the datasheet

Chang Gung Memorial Hospital

Associated Professor

Neoplasms

Gland and Hormone Related Diseases

Digestive System Diseases

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Rectal Neoplasms

Appendiceal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Cecal Neoplasms

Cecal Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Exercise: The exercise training program was designed to improve physical fitness prior to surgery and for a 6-week period after surgery once deemed fit.

Nutrition: The nutritional arm consists of nutritional intervention tailored to the outcome of the nutritional screening.Participants will be asked to take part in a dietary food recall system called Foodbook24, and based on their dietary needs will be supported in nutritional optimisation.

This group will receive standard oncological care and will receive no formal education of exercise or nutritional intervention.

Standard Exercise Program- Participants will be invited to take part in a structured home, supervised, or both, exercise program while undergoing treatment and for a six-week period when deemed fit post-surgery.

Exercise

Participants will be screened for their nutritional health and tailored advice and education will be provided on an individualised basis. An online dietary recall tool will be used to track patients' dietary habits. This will occur from diagnosis until point of surgery and recommence for 6 weeks post-surgery once deemed physically fit.

Nutrition

Jurgen Mulsow, Mr.

Lisa Loughney, Dr.

Lorraine Boran, Dr.

People who are diagnosed with cancer of the colon/rectum/appendix/ovaries that spreads into the lining of the tummy and some ovarian cancers or people with pseudomyxoma peritonei can often undergo intensive treatment including major surgery where chemotherapy is given whilst the person is having surgery - also known by doctors as surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Fitness for this surgery can improve if people undertake a prehabilitation programme at the time they get their diagnosis. To date, little research has focused on how exercise and nutrition support before surgery can help these patients during recovery. The aim of this study is to explore the use of exercise and nutritional support pre-treatment to enhance physical and psychological outcomes for patients.

The comparator in this study will be standard oncological care. Control patients will receive the same care as standard without the addition of a formal exercise and nutrition support programme. The pre-treatment (prehabilitation) programme will commence following diagnosis and continue up to the point of surgery and recommence for six weeks following surgery when deemed clinically fit to participate. Assessments will occur at baseline, pre-surgery, post-surgery, and 6 weeks later and a follow up... Mixed methods will be employed with patients taking part in self-report assessments, physical assessments, and qualitative interviews. The primary aim of the study is to assess the feasibility of the intervention and cardiorespiratory fitness pre-surgery. The secondary aims include assessing the effect of the intervention on physical health, psychological wellbeing, health-related quality of life, self-efficacy, nutrition, and serology markers. Exploratory aims also include post-operative morbidity, health economics analysis and qualitative interview of patient experience.

Parallel group randomised 1:1 controlled multi-centre trial

It will not be possible to be blinded to the to the allocation of participants due to their active involvement in the behavioural exercise and nutritional interventions during the study.

Perioperative Exercise and Nutritional Optimisation Prehabilitation Before Surgery for Patients With Peritoneal Malignancy

The PANO Trial: Perioperative Exercise and Nutrition Optimisation Prehabilitation in Cancer Patients With Peritoneal Malignancy

This is an 18-item tool that addresses morbidity relevant to the post-surgical patient.

This is a classification of surgical complications with seven grades. The Comprehensive Complication Index (CCI) sums all post-operative complications with their respective severities on a scale of 0 (no burden) to 100 (fatality).

The Comprehensive Complication Index (CCI) sums all post-operative complications with their respective severities on a scale of 0 (no burden) to 100 (fatality).

Length of stay in hospital as a result of their operation.

An exploratory analysis will review healthcare resource use by individual participants and with locally determined unit cost calculate the healthcare cost related to the two interventions. The mean group difference in accumulated costs will be used in the cost-effectiveness analysis.

Biomarkers will be analysed on a sub-group (n=20) of recruited participants. Serological markers of inflammation using a multiplexed ELISA approach will be measured. The Luminex system can measure up to 45 serum cytokines and markers of inflammation, including the inflammatory cytokine IL-6, which has been associated with increased PS and PA. Inflammatory markers will be assessed at baseline, pre-surgery and post-surgery and 6 weeks post. Blood samples are taken routinely pre and post-surgery but for the purpose of the study the two additional timepoints of baseline/consent and 6 weeks post will also be taken. Using this dynamic approach, we will be able to correlate a patient's inflammatory response with their outcome during their prehabilitation and after surgery.

Patients will also be asked whether they consent to take part in a short semi-structured phone interview with a member of the research team across two timepoints: pre surgery and 6 weeks post. The interviewer will ask the patients exploratory questions relating to four main topics: 1) Participants experiences and engagement with their care pathway (both control and intervention) 2) Perceptions of their emotional and physical preparation before surgery 3) Perceptions of their condition pre and post-surgery 4)Perceptions of physical and emotional symptoms pre and post-surgery.

Participants will be asked for their smoking status. If participants are active smokers who would like to cease smoking, they will be provided with the National Centre for Smoking Cessation and Training information support packages.

Prehabilitation fidelity in terms of the patient group adherence as measured by patient structured qualitative feedback and activity logs.

Prehabilitation fidelity in terms of the patient group retention as measured by patient screening and retention logs and monitoring of recruitment rates.

Prehabilitation fidelity in terms of intervention effectiveness as measured by qualitative patient feedback at two timepoints. Monitoring of patient activity logs. Engagement with online and in-person exercise and nutritional intervention resources.

Cardiorespiratory fitness using the 6-Minute Walk Test (6MWT) assessed at the pre-surgery time point. The 6MWT is performed with participants walking up and down a 20 m course marked by cones for 6 min under instruction to cover as much ground as possible. The number of laps completed is recorded. A standard set of instructions is used as per the European Respiratory Society guidelines. The 6MWT is a validated assessment of cardiorespiratory function in clinical populations.

This is measured using a hand dynamometer. The test will be conducted in a standing position with the upper arm tight against the participant's trunk and the forearm at a right angle to the upper arm. If this is not possible the participant may sit in an upright chair or use their free hand to rest the dynamometer on a table to support the arm. The gripping handle will be set to a comfortable width to ensure the patient can rest the middle piece of the four fingers on the handle. The participant will be instructed to squeeze the handle with maximum force for a few seconds. The value on the scale will be recorded. The participant will complete two trials on each hand. The highest score will be accepted.

Participants will sit on a chair (height 43-45 cm) with arms crossed on their, and legs flat on the floor, parallel to each other, and approximately shoulder width apart. Participants will stand up and sit down 10 times as quickly as possible. Participants must not bounce off the chair when moving from a seated position to standing position. They must fully extend their legs on each stand. The time taken to perform 10 repetitions will be timed using a stopwatch. Participants will perform two trials and the best trial will be recorded as their score.

Participants will be instructed to wear the device on the midpoint of the anterior aspect of the right thigh and attach using a film adhesive frame dressing. They will continue to wear this for three days continuously. They cannot wear the ActivPAL3 triaxial accelerometer during water activity periods.

NCCN Distress Thermometer: To detect distress (psychosocial stress) with all stages of cancer. This is measured using a visual analogue scale like a thermometer to indicate a range from 0 (not loaded) to 10 (extreme pressure). Additional 36 items in five problem areas - practical family, emotional, spiritual, physical, are rated for distress and a score of 5 or higher is considered significant stress.

This is a self-report measure of traumatic stress symptoms focused on intrusive thoughts and avoidant behaviours. Questions will be adapted to reflect the PM diagnosis specifically. Frequency of symptoms will be self-reported during the previous week using a 4 point scale from 0 (not at all) to 5 (often). Total scores range from 0 to 75 with higher scores indicative of greater cancer-related stress. Scores in the range of \> 30 are reflective of clinically significant stress. Higher scores on an adapted IES are related to decreased immune function in breast cancer patients.

This questionnaire is a semi-structured interview with the patients that measures reserve in three parts: Education; Working-Activity, and Leisure time. Each sub-scale and total index score is correlated with age and expressed on a standardised scale.

The Functional Assessment of Cancer Therapy- Cognition is a self-report 37 item questionnaire that assesses cancer related cognitive problems. Sub-scales include: Perceived cognitive impairments, impact of perceived cognitive impairments on QoL, Comments from others and perceived cognitive abilities.

This is a 12 item Communication and Attitudinal Self-Efficacy scale for Cancer, and rates a patients' perceived ability to seek information, understand and engage in care, and maintain a positive attitude. Confidence level for each skill is rated on a 4 point scale with higher score indicative of higher self-efficacy.

This is a standardised and validated self-report measure describing health status. It is disease non-specific but applicable to cancer, with five dimensions (mobility, self-care, typical activities, pain, anxiety/depression) with three problem levels to rate (some to extremely problematic). The higher the index score, the higher the perceived health status.

This is a version of the Functional Assessment of Cancer Therapy is a 28-item self-report survey that measures quality of life; it has 5 sub-scales measures physical well-being (PWB), functional wellbeing (FWB), social/family wellbeing (SFWB), emotional wellbeing (EWB) and satisfaction with care. Self-ratings of all 5 subscales for the present moment and the preceding week are captured, computing an overall total score. Good Cronbach's for all five have been reported, and the higher the core the better the QoL.

The Malnutrition Screening Tool (MST) is an easy to administer tool. It is based on recent appetite and weight loss and has been previously validated for use with oncology patients. The measure scores both "recent intake" and "recent weight loss". A total score of \>2 indicates a risk of malnutrition.

This measure of cancer prognosis is measured using serum markers CRP and Albumin. The score is used to measure the cancer prognosis. The score ranges from 0-2, with patients with a normal measure of CRP assigned a score of zero, and those with both elevated or reduced levels a score of 2.

Foodbook24 is a Web-based, dietary tool consisting of a 24-hour dietary recall and food frequency questionnaire. Patients will provide dietary recall information about what they have eaten in the past 24 hours.

Bloods should be ordered by clinician for Iron (Fe) analysis (identify anaemia) and CT scans of patients should be analysed for the identification of incidence of sarcopenia.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Risk of Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy	NCT04941625	Acute Kidney In...	serum cystatin ... serum beta-micr... urine	20 Years - 75 Years	Chang Gung Memorial Hospital
Risk of Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy	NCT04941625	Acute Kidney In...	serum cystatin ... serum beta-micr... urine	20 Years - 75 Years	Chang Gung Memorial Hospital
Perioperative Exercise and Nutritional Optimisation Prehabilitation Before Surgery for Patients With Peritoneal Malignancy	NCT05305820	Peritoneal Mali... Ovarian Cancer Rectum Cancer Appendix Cancer Colon Cancer	Exercise Nutrition	18 Years -	Dublin City University

Spots Global Cancer Trial Database for peritoneal malignancy