Clinical trial NCT02551237: Neoadjuvant Treatment for Advanced Rectal Carcinoma
Official title: A Phase III Study Evaluating Two Neoadjuvant Treatments Radiochemotherapy (5 Weeks - 50Gy+Capecitabine) and Radiotherapy (1week - 25Gy) in Patient Over 75 With Locally Advanced Rectal Carcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rectal Carcinoma
Keywords: Elderly patient
Radiotherapy
Radio chemotherapy
Neoadjuvant treatment
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2015-09-16
Enrollment: 103
Sex: ALL
Minimum age (years): 75
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to compare pre-operative radio-chemotherapy (RT + capecitabine) to a short course RT associated with a delayed surgery, with two primary objectives: the efficacy evaluation (rate of R0 resection) and the preservation of autonomy (score IADL).

Detailed description: Colorectal cancer is one of the most frequent cancers diagnosed in France. The average age of diagnosis in 2012 was 70 years old for men and 73 years for women, confirming that colorectal cancer is a disease of the elderly population.

The literature concerning combined treatments of colorectal cancer in the elderly is extremely limited. The application of combined treatments in the geriatric population is associated with an increase in the therapeutic complications. These post-operative complications together with the comorbidities and age are unfavorable prognostic factors for survival in patients with cancer of the rectum; this explains why the improved results obtained during the last decades are perceptible in younger patients and not in the elderly.

In the general population, pre-operative radio-chemotherapy has imposed itself as a standard treatment for the cancer of the rectum locally advanced. The utilization of fluoropyrimidines associated with radiotherapy (RT) delivered in fractions \[long course RT (50 Gy in 5 weeks), surgery planned 6 to 8 weeks later\] increases the complete histological response rate and decreases significantly the rate of local relapse.

The short-course RT \[short course RT using the Swedish model (5x5 Gy in 5 days), with the surgery programmed the following week\] is the standard neoadjuvant protocol in an important number of countries and/or academic groups. The studies that have compared the fractioned RT scheme to the short-course RT protocols have not shown any evidence of a change in efficacy of the short course RT concerning the following criteria: rate of R0 resection, rate of sphincter conservation, rate of relapse at 3 years, the disease free survival or the overall survival. Similarly, there appears to be no difference in severe toxicities in the long term. It should however be noted that short-course RT followed by immediate surgery may be less efficient than combined treatment in patients with a distal T3 cancer, even though these conclusions published by Ngan have been criticized by certain. On the other hand, the fractioned combined treatments results in more tumor and stage reduction and thus more sterilization.

Nevertheless a retrospective analysis, performed in the Stockholm region, in patients irradiated with short-course protocol but operated with a delay of at least 4 weeks resulted in a sterilization rate of 8%. This result is even more interesting since in this cohort, 46% of the patients had a tumor classified T4 and that 38% of the patients had a primitive tumor considered inoperable.

In the elderly population, the neoadjuvant treatment has rarely been studied. An exploratory analysis of the PRODIGE 2 study, based on age as the criteria, has shown that pre-operative radio-chemotherapy is significantly more toxic in the elderly population, from 70 years of age. Globally the lower tolerance for the pre-operative radio-chemotherapy results in more frequent early termination of RT and a statistically significant decrease in the number of patients operated. Furthermore, if the type of surgery was not significantly different between patients \<70 years and those ≥70 years, we observe a non-significant increase in the rate of prolonged stoma (patients amputated without closure of the stoma). These differences in the surgical procedures is also observed in other publications, placing the emphasis on the fact that in the absence of any difference in the clinical presentation or the characteristic of the tumor, the risk of real or supposed decompensation modifies the surgical care. These data, as well as those in the literature, provides evidence that the pre-operative radio-chemotherapy strategy followed by surgery, the standard strategy in younger patients, is associated with more side effects in the elderly, resulting in the benefit-risk balance, in this population, to be more questionable.

It is therefore necessary to conduct a specific studies in the elderly population, with cancer of the rectum with the objective to maintain the carcinological results obtained with classical radio-chemotherapy with at the same time better controlling the secondary effects of the treatment and the risk of decompensation of the patients: the short course radiotherapy associated with a delayed surgery may be a therapeutic scheme well adapted to this population.

The investigators therefore propose a study comparing pre-operative radio-chemotherapy (RT + capecitabine) to a short course RT associated with a delayed surgery, with two primary objectives: the efficacy evaluation (rate of R0 resection) and the preservation of autonomy (score IADL).

Eligibility criteria: Inclusion Criteria:

* Patient ≥75 years
* Eastern Cooperative Oncology Group (ECOG) ≤2
* Adenocarcinoma of the rectum histologically proven
* Tumor ≤12 cm from the anal margin, the measurement done by rigid rectoscopy or by sub peritoneal MRI
* Require a pre-operative treatment (tumor classified T3 or T4 resectable by MRI and tomodensitometry or T2 of the very low rectum)
* Patient operable
* No radiologically detectable metastases
* Absolute Neutrophile count (ANC) ≥1500/mm³; Platelets ≥100 000/mm³ and Hemoglobin ≥10 g/dL
* Bilirubin ≤1.5 x upper limit of normal (ULN), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤1.5 x upper limit of normal (ULN), Alkaline Phosphatase ≤1.5 x upper limit of normal (ULN)
* Creatinine clearance ≥30 ml/min (Cockcroft and Gault)
* Uracilemia \< 16ng/mL
* Public or private Health Insurance coverage
* Patient has been informed and signed the informed consent document

Exclusion Criteria:

* Non-resectable tumor
* History of chronic diarrhea or an inflammatory disease of the colon or rectum, or intestinal obstruction or sub-obstruction
* History of pelvic radiotherapy
* Any active febrile infection or any other serious underlying pathology that may prevent the patient from receiving the treatment
* Significant Cardiovascular diseases such as, but not limited to: cardiovascular or myocardial infarction ≤6 months before inclusion, congestive heart failure class II or higher (NYHA), unstable angina, arrhythmia requiring medication or uncontrolled hypertension;
* Significative cardiovascular conditions such as, but not limited to : Cardiac angioplasty or stenting, Myocardial infarction, Unstable angina, Coronary artery bypass graft surgery Symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA), clinically significant irregular heartbeat requiring medication
* Severe and unexpected reactions to fluoropyrimidine therapy
* Any contra-indication to capecitabine and its excipients; patients with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not included.
* Uracilemia ≥ 16ng/mL
* Any other concomitant cancer or history of cancer in the last 3 years, with the exception of the in situ cancer of the uterus, treated, or squamous-cell or basal-cell carcinoma.
* Patients already included in another therapeutic trail with an experimental molecule
* Person deprived of liberty
* Patient that for geographical, social and/or physical reasons will not be able to follow the procedure as required by the protocol

Primary outcomes:
measure: R0 resection rate
timeFrame: 3 months
measure: IADL (Instrumental Activities of Daily Living) Score
timeFrame: 1 year
Secondary outcomes:
measure: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.03
timeFrame: 3 months
measure: Post-operative complications
timeFrame: 3 months
measure: Death rate
timeFrame: at 6 and 12 months
measure: Overall survival (OS)
timeFrame: 10 years
measure: Specific survival
timeFrame: 10 years
measure: Disease free survival
timeFrame: 10 years
measure: Loco-regional disease free survival
timeFrame: 10 years
measure: Rate of stoma
timeFrame: at 6 and 12 months
measure: Instrumental Activities of Daily Living (IADL)
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Activities of Daily Living (ADL)
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Questionnaire G8
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Mini-Mental Score Examination (MMSE)
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Walking gate
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Geriatric Depression Scale (GDS15)
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Charlson score
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: Mini Nutritional Assessment (MNA)
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
measure: EORTC QLQ-C30 + EDL14
timeFrame: Baseline, within 2 weeks before surgery and 3, 6 and 12 months after surgery
Other outcomes:
Locations:
city: Abbeville
country: France
facility: Centre Hospitalier d'Abbeville
city: Albi
country: France
facility: Clinique Claude Bernard
city: Amiens
country: France
facility: CHU Amiens Picardie
city: Bastia
country: France
facility: Polyclinique Maymard
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Besancon
country: France
facility: CHU de Besançon
city: Blois
country: France
facility: Cebtre Hospitalier de Blois
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Créteil
country: France
facility: CHU Henri Mondor
city: Dax
country: France
facility: Centre Hospitalier de Dax
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Dijon
country: France
facility: CHU DIJON (Hôpital du Bocage)
city: GAP
country: France
facility: CHIC des Alpes du Sud- site de Gap
city: Grenoble
country: France
facility: CHU de Grenoble Hôpital A Michallon
city: Hyeres
country: France
facility: Hôpital Privé Sainte Marguerite
city: La Roche-sur-yon
country: France
facility: CHD de Vendée
city: Levallois-perret
country: France
facility: Institut Hospitalier Franco-Britannique
city: Limoges
country: France
facility: Centre Hospitalier Universitaire de Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
city: Marseille
country: France
facility: CHU Timone
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Mougins
country: France
facility: Centre azuréen de cancérologie
city: Neuilly-sur-seine
country: France
facility: Hôpital Américain de Paris
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nimes
country: France
facility: Chu Caremeau
city: Nîmes
country: France
facility: Centre Médical Oncogard Institut de cancérologie du Gard
city: Paris
country: France
facility: Hôpital TENON
city: Pessac
country: France
facility: CHU de Bordeaux
city: Pringy
country: France
facility: Centre Hospitalier Annecy Genevois
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Mande
country: France
facility: Hôpital d'instruction des Armées
city: Toulouse
country: France
facility: Clinique Pasteur
city: Vandoeuvre Les Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy Cancer Campus Grand Paris
Study officials:
affiliation: Centre Antoine Lacassagne
name: Eric Francois
role: PRINCIPAL_INVESTIGATOR
References: