Clinical trial NCT04305314: Long-term Enlarged Survival After an Enhanced Recovery Protocol (LESAS).
Official title: Surgical Treatment of Colorectal Cancer: Analysis of the Influence of an Enhanced Recovery Protocol on Long-term Oncological Outcomes.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Major Surgery
Lead sponsor: Grupo Español de Rehabilitación Multimodal
Sponsor class: OTHER
Collaborators: name: Instituto de Salud Carlos III
name: Instituto de Investigación Sanitaria Aragón
First posted: 2020-03-12
Enrollment: 750
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Multicenter prospective observational cohort study in patients who meet inclusion criteria (18 years of age who will be operated on a scheduled basis for colorectal cancer ) in participating hospitals

Brief summary: The main objective of this study is to analyze the impact on three years survival of an enhanced recovery program (PRI) after radical surgery for colorectal cancer. As secondary objectives, we propose to analyze the weight of each of the predefined items in the oncological results as well as the quality of life.

We design a multicentric prospective cohort study in people older than 18 years who are going to be operated on for colorectal cancer. 12 hospitals are being selected due to have a PRI implanted according to the RICA pathway published by the Spanish National Health Service. As stated by the literature, the intervention group will be formed for those hospitals with a minimum implementation level of 70% of the PRI and the control group will be the centers that do not reach this level of implementation. Compliance will be studied with 21 key performance indicators and results are analyzed with cancer survival indicators: Overall survival, cancer-specific survival and relapse-free survival). We will also study the time to recurrence, perioperative morbi-mortality, hospital stay and quality of life with the EQ-5D validated questionary.

To create comparable treatment and control groups, the Propensity Index method will be used. To study each variable, multivariate regression will be used. Kaplan-Meier will be used for survival and the log-rank test for comparisons. Significance will be considered if p \<0.05 (two tails).

Detailed description: Subjects of study (inclusion criteria): All patients over 18 years of age who will be operated on a scheduled basis for colorectal cancer within an intensified recovery program (PRI) and who do not present any exclusion criteria.

Exclusion Criteria: - Urgent surgery; -Existence of other concomitant surgical processes; -Patients diagnosed in stage IV cancer; -Patients who refuse to participate.

Participating hospitals: Selected for their interest in intensified recovery and for having established a multidisciplinary team with the program (PRI) for colorectal surgery recommended by the Spanish Ministry of Health. Each center will select from the multidisciplinary team the researchers who will be part of this project as collaborators, ideally the facilitators of the PRI program in that center.

Variables: Patients will be recruited by local researchers from the Anesthesiology and Resuscitation and/or General Surgery services of each participating center before performing the surgical intervention. Informed consent will be requested from all subjects who voluntarily participate in the study.

1. Compliance: As we have commented before and according to the literature, we will define a hospital with an intensified recovery program (PRI) that has a consensus protocol, based on evidence, multidisciplinary, with the support of the center (management) and that has fulfilled more than 70% of the protocol (annex 1) according to the process indicators. The rest of the hospitals will be considered a non-PRI hospital.
2. Demography: Age, sex, BMI, smoking and fitness level of the American Society of Anesthesiologists (ASA). BMI in the surgical indication. Blood transfusion.
3. Comorbidities: Presence of hypertension, diabetes mellitus, coronary artery disease, heart failure, cirrhosis, stroke or transient ischemic attack, COPD / Asthma, atrial fibrillation, heart failure, OSAS. Anemia
4. Related to Surgery and Treatment: Date IQ. Surgical procedure, approach, duration of surgery, estimated bleeding. Curative surgery (R0) or non-R0 (R1-R2). Adjuvant chemotherapy Adjuvant radiotherapy Perioperative transfusion.
5. Variables related to staging: Tumor typology. Growth pattern. Degree of differentiation. Presence of Vascular / lymphatic / perineural invasion / Satellites. Margin affectation. Seal ring cells. K-ras. T tumor piece. No tumor piece. Tumor m. Tumor stage according to AJCC classification.
6. Related to the follow-up:

In-hospital complications at 60 days of follow-up that will be recorded are: surgical complications, infectious complications, cardiovascular complications and other types of complications. Each complication will be classified as mild, moderate or severe. The Clavien-Dindo classification will also be used. Perioperative mortality: The number and percentage of deaths within 60 days of surgery. Hospital Stay: hospital stay is defined as the duration in days from the date of admission to hospital discharge. Quality of life according to the EuroQol Five questionnaire. (EQ-5D).

Overall mortality: The number and percentage of deaths occurred since the intervention until the end of the follow-up period. Overall survival: patients alive from surgery to the last control. Disease-free survival: number of patients alive and without cancer recurrence from the intervention period until the end of follow-up.

Disease recurrence: detected by CT or FCC, from the day of the intervention until the end of the follow-up.

Patient Follow-up Plan: 5 years after surgery. Data collection: The data will be collected in individual hospitals on a paper CRD for each patient recruited. This will include patient identification data in order to allow monitoring of clinical results. The data will be encoded by generating a unique numerical code and transcribed by local researchers in a database using an electronic CRD (eCRD). The data collection platform used will be Castor EDC https://www.castoredc.com/. Castor EDC complies with all applicable laws and regulations: good clinical practice (GCP), 21 CFR Part 11, EU Annex 11 and the European Data Protection Directive. Each patient will only be identified in the electronic CRD by their numerical code. In each center a list of patients will be used to match the identification codes of the individual patients' database in order to record the clinical results and provide any of the missing data. All identifiable data collected, processed and stored for the purposes of the project will be kept confidential at all times and will comply with the guidelines of Good Clinical Practice for Research (GCP) and the General Data Protection Regulation (GDPR) (Regulation (EU) ) 2016/679).

Data analysis: Sample size: understanding, according to the literature, that only 60% of the centers with a PRI achieve more than 70% of compliance, we consider the scenario of 6 PRI and 4 non-PRI centers adequate among the 10 who collaborate in this research project. Estimating a difference in overall survival between centers around 10% (65% vs. 75%), with a power of 80%, a 95% confidence and 5% of possible losses, a minimum sample size of 366 is estimated patients in each group (732 patients in total). For the study of survival, only patients with a minimum follow-up of two years (first 12 months of the study) will be considered. However, they will continue to be recruited until the end of the three years for the study of secondary objectives.

Understanding that the main objective, study of survival, may be subject to inherent aspects of each center, independent of the intervention, it is necessary to create comparable treatment and control groups for which the Propensity Score (Propensity Score Matching) method will be used. A descriptive analysis of the data will be carried out: Qualitative variables will be presented by frequency distribution of the percentages of each category. The quantitative variables studied will be explored with the Kolmogorov - Smirnov conformity test. Bivariate Analysis Comparison between variables (factors): The association between the factors will be investigated by hypothesis contrast tests, with comparison of proportions when both variables are qualitative (chi square, Fisher's exact test), mean comparisons when one of them is quantitative (Student's t, ANOVA, and if they do not follow the normal distribution, the Mann-Whitney U test or the Kruskall-Wallis test) and bivariate correlations (Coef. Pearson Correlation) when both are quantitative or, if the conditions are not met of application, the Spearman correlation. For comparisons in related samples when one of them is quantitative, Student's t-test and/or ANOVA will be used for repeated measurements and Wilcoxon or Friedman's test when do not follow normal distribution). Multivariate analysis: To study the relationship of each variable controlling the possible effect caused by third variables. The analysis will be completed using multivariate regression models. Survival analyzes will be performed using the Kaplan-Meier method for survival comparisons the log-rank test will be used. The effects will be considered significant if p \<0.05.

Monitoring and audit: The data collection documents will be audited to ensure that study activities are carried out in accordance with the protocol, good clinical practice and applicable regulatory requirements. In the participating hospitals, local study documents can be selected for local auditing. The quality of the data will be audited.

Limitations of the study: Those of a prospective non-randomized study. Difficulty in recruiting patients for potential structural or multidisciplinary team problems. Inappropriate number of patients in any of the arms due to a very high or very low level of compliance.

Eligibility criteria: Inclusion Criteria:

* All patients over 18 years of age who will be operated on a scheduled basis for colorectal cancer

Exclusion Criteria:

* - Urgent surgery; -Existence of other concomitant surgical processes; -Patients diagnosed in stage IV cancer; -Patients who refuse to participate.

Primary outcomes:
measure: Overall Survival
timeFrame: 5 years
measure: Disease-free survival
timeFrame: 5 years
measure: Disease recurrence
timeFrame: 5 years
Secondary outcomes:
measure: Compliance of individual items of the protocol
timeFrame: 5 years
measure: Quality of Life (QOL)
timeFrame: 5 years
measure: Patient reported outcoms (PROs)
timeFrame: 5 years
Other outcomes:
Locations:
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Pamplona
country: Spain
facility: Complejo Hospitalario de Navarra
state: Navarra
city: Alzira
country: Spain
facility: Hospital de la Ribera
city: Barbastro
country: Spain
facility: Hospital de Barbastro
city: Guadalajara
country: Spain
facility: Hospital Universitario de Guadalajara
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Jiménez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario Infanta Leonor
city: Palencia
country: Spain
facility: Complejo Asistencial Universitario de Palencia
city: Valencia
country: Spain
facility: Hospital General de Valencia
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Universidad de Zaragoza
name: Jose M Ramirez, Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ramirez-Rodriguez JM, Martinez-Ubieto J, Munoz-Rodes JL, Rodriguez-Fraile JR, Garcia-Erce JA, Blanco-Gonzalez J, Del Valle-Hernandez E, Abad-Gurumeta A, Centeno-Robles E, Martinez-Perez C, Leon-Arellano M, Echazarreta-Gallego E, Elia-Guedea M, Pascual-Bellosta A, Miranda-Tauler E, Manuel-Vazquez A, Balen-Rivera E, Alvarez-Martinez D, Perez-Pena J, Abad-Motos A, Redondo-Villahoz E, Biosta-Perez E, Guadalajara-Labajo H, Ripolles-Melchor J, Latre-Saso C, Cordoba-Diaz de Laspra E, Sanchez-Guillen L, Cabellos-Olivares M, Longas-Valien J, Ortega-Lucea S, Ocon-Breton J, Arroyo-Sebastian A, Garcia-Olmo D. Surgical treatment for colorectal cancer: analysis of the influence of an enhanced recovery programme on long-term oncological outcomes-a study protocol for a prospective, multicentre, observational cohort study. BMJ Open. 2020 Oct 27;10(10):e040316. doi: 10.1136/bmjopen-2020-040316.