| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Primary rectal cancer with high risk of failing locally and/or
systemically |
| Cáncer rectal primario con alto riesgo de fracaso local o sistémico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary rectal cancer |
| Cancer rectal primario |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038038 |
| E.1.2 | Term | Rectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To increase the disease-free survival after 3 years follow-up. |
Aumentar la supervivencia libre de enfermedad después de 3 años de
seguimiento. |
|
| E.2.2 | Secondary objectives of the trial |
To describe the toxicity profile of the combined modality treatment in schedule.
To determine the completion rate of the neo-adjuvant treatment.
To determine the fraction of patients with a radical resection (negative CRM)
To determine the pathological complete response rate (pCR).
To determine the postoperative complications
To describe the local recurrence rate after 3 years follow-up.
To evaluate quality of life.
To evaluate functional outcome.
To increase overall survival after 5 years of follow-up. |
Describir el perfil de toxicidad del programa de tratamiento con la modalidad
combinada.
Determinar la tasa de finalización del tratamiento neoadyuvante.
Determinar la fracción de pacientes con una resección radical (MCR negativo).
Determinar la tasa de respuesta completa anatomopatológica (RCa).
Determinar las complicaciones postoperatorias.
Describir la tasa de recidiva local después de 3 años de seguimiento.
Evaluar la calidad de vida.
Evaluar el resultado funcional.
Aumentar la supervivencia global después de 5 años de seguimiento. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Primary tumour characteristics
Biopsy-proven, newly diagnosed primary rectal adenocarcinoma, i.e. with the lowest part of the tumour less than 16 cm from the anal verge using a rigid rectoscope or flexible endoscope.
Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically:
o Clinical stage (c) T4a, i.e. overgrowth to an adjacent organ or structure like the
prostate, urinary bladder, uterus, sacrum, pelvic floor or side-wall (according to
TNM version 5).
o cT4b, i.e. peritoneal involvement.
o Extramural vascular invasion (EMVI+).
o N2, i.e. four or more lymph nodes in the mesorectum showing morphological
signs on MRI indicating metastatic disease. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient.
o Positive MRF, i.e. tumor or lymph node one mm or less from the mesorectal
fascia.
o Metastatic lateral nodes, > 1 cm (lat LN+)., see appendix G
General
Staging done within 5 weeks before randomization.
No contraindications to chemotherapy, including adequate blood counts:
- white blood count > or = 4.0 x 109/L
- platelet count > or =100 x 109/L
- clinically acceptable haemoglobin levels
- creatinine levels indicating renal clearance of > or =50 ml/min
- bilirubin < 35 μmol/l.
ECOG performance score < or = 1, see appendix B.
Patient is considered to be mentally and physically fit for chemotherapy as judged by the oncologist.
Age > or = 18 years
Written informed consent.
Adequate potential for follow-up. |
Características del tumor primario
Adenocarcinoma rectal primario recién diagnosticado y demostrado mediante
biopsia, es decir, con la parte inferior del tumor a menos de 16 cm de distancia del borde anal utilizando un rectoscopio rígido o un endoscopio flexible.
Tumor localmente avanzado que cumple al menos uno de los criterios siguientes en la RM pélvica, indicativo de alto riesgo de fracaso local o sistémico:
o Estadio clínico (c) T4a, es decir, propagación a un órgano o estructura
adyacente como la próstata, la vejiga urinaria, el útero, el sacro, el suelo
pélvico o la pared lateral (según la versión TNM 5).
o cT4b, es decir, afectación peritoneal.
o Invasión vascular extramural (IVEM+).
o N2, es decir, cuatro o más ganglios linfáticos en el mesorrecto con signos
morfológicos en la RM indicativos de enfermedad metastásica. Por
consiguiente, no es suficiente con la presencia de cuatro o más ganglios,
agrandados o no, de aspecto redondeado y homogéneo.
o FMR positiva, es decir, tumor o ganglio linfático a una distancia de 1 mm
o menos de la fascia mesorrectal.
o Ganglios mestastasicos laterales > 1 cm (lat LN+), véase apendice G
Requisitos generales
La estadificación se realizará en las 5 semanas anteriores a la aleatorización.
No podrán existir contraindicaciones para la quimioterapia, como unos recuentos sanguíneos insuficientes:
o recuento de leucocitos ≥ 4,0 x 109/l
o recuento de plaquetas ≥ 100 x 109/l
o cifras de hemoglobina clínicamente aceptables
o concentraciones de creatinina indicativas de un aclaramiento renal de
≥ 50 ml/min
o bilirrubina < 35 μmol/l.
Puntuación del estado general ECOG ≤ 1, véase el apéndice B.
Se considera que el paciente está mental y físicamente capacitado para recibir
quimioterapia a criterio del oncólogo.
Edad ≥ 18 años
Consentimiento informado por escrito.
Posibilidades razonables de seguimiento |
|
| E.4 | Principal exclusion criteria |
Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen.
Presence of metastatic disease or recurrent rectal tumour. Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn’s disease or active ulcerative Colitis.
Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years.
Known DPD deficiency.
Any contraindications to MRI (e.g. patients with pacemakers).
Medical or psychiatric conditions that compromise the patient’s ability to give informed consent.
Concurrent uncontrolled medical conditions.
Any investigational treatment for rectal cancer within the past month.
Pregnancy or breast feeding.
Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract.
Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months.
Patients with symptoms or history of peripheral neuropathy. |
Crecimiento extenso en la parte craneal del sacro (por encima de S3) o en las raíces nerviosas lumbosacras, lo que indica que la cirugía no será nunca posible, ni siquiera aunque se consiga una reducción importante del tamaño del tumor.
Presencia de enfermedad metastásica o tumor rectal recidivante. Poliposis
adenomatosa familiar (PAF) cólica, cáncer colorrectal no polipósico hereditario
(CCNPH), enfermedad de Crohn activa o colitis ulcerosa activa.
Neoplasias malignas concomitantes, excepto carcinoma basocelular de la piel
tratado adecuadamente o carcinoma de cuello uterino in situ. Los pacientes con
antecedentes de neoplasias malignas tienen que estar libres de enfermedad desde hace por lo menos 5 años.
Deficiencia confirmada de DPD.
Cualquier contraindicación para la RM (por ejemplo, pacientes con marcapasos).
Trastornos médicos o psiquiátricos que comprometan la capacidad del paciente para otorgar su consentimiento informado.
Trastornos médicos concomitantes no controlados.
Cualquier tratamiento experimental para el cáncer rectal recibido en el último mes.
Embarazo o lactancia.
Pacientes con síndromes conocidos de malabsorción o ausencia de integridad física del tubo digestivo alto.
Cardiopatía clínicamente significativa (es decir, activa) (por ejemplo, insuficiencia cardíaca congestiva, enfermedad coronaria sintomática y arritmia cardiaca, por ejemplo, fibrilación auricular, aunque se controle con medicación) o infarto de miocardio en los últimos 12 meses.
Pacientes con signos o antecedentes de neuropatía periférica. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease-free survival after 3 years follow-up is the primary endpoint. |
| El criterio de valoración principal es la supervivencia sin enfermedad después de 3 años de seguimiento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Disease-free survival will be computed as the time between randomization and either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. Patients lost to follow-up will be censored the last date of patient visit. |
La supervivencia sin enfermedad se calculará como el tiempo transcurrido entre la
aleatorización y la recidiva local o a distancia o la muerte causada por el carcinoma
rectal, lo que ocurra antes. En el caso de muerte relacionada con un cáncer no rectal, se censurará a los pacientes fallecidos en la fecha de su muerte. En el caso de un segundo tumor primario, se censurará a los pacientes en la fecha del diagnóstico del segundo tumor primario. Los pacientes perdidos para el seguimiento serán censurados en la fecha de la última visita del paciente. |
|
| E.5.2 | Secondary end point(s) |
Treatment associated toxicity, including surgical morbidity
Completion rate of neo-adjuvant treatment
Negative CRM (margin > 1 mm)
pCR
Postoperative complications
Local recurrence at 3 years
Overall survival
Functional outcome
Quality of life |
Toxicidad asociada al tratamiento, incluida la morbilidad quirúrgica
Tasa de finalización del tratamiento neoadyuvante
MCR negativo (margen 1 mm)
RCa
Complicaciones postoperatorias
Recidiva local a los 3 años
Supervivencia global
Resultado funcional
Calidad de vida |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Toxicity:All patients will be evaluable for toxicity from the time of their first treatment.
Fraction of radical resection (CRM > 1 mm): will be evaluated according the pathology protocol described by Quirke et al.
Complete pathological response (pCR):is done by the method described in section 6.
Local recurrence: is described as relapse of tumour in the pelvic region.
Distant relapse: is described as relapse of tumour outside the pelvic region.
Local control: will be computed as the time between randomization and local relapse.
Overall survival: will be computed as the time between randomization and all causes of death.
Quality of Life (QoL):including functional outcome will be studied as described in Chapter 8 |
| Toxicidad:Todos los pacientes serán evaluables para el análisis de toxicidad desde el momento en que reciban su primer tratamiento. MCR > 1 mm:se evaluará según el protocolo de anatomía patológica descrito por Quirke y cols. RCa:se basa en el método descrito en el apartado 6. Recidiva local:se describe como recidiva del tumor en la región pélvica. Recidiva a distancia: se describe como una recidiva tumoral fuera de la región pélvica. Control local: se calculará como el tiempo transcurrido entre la aleatorización y la recidiva local. Supervivencia global: se calculará como el tiempo transcurrido entre la aleatorización y la muerte del paciente por cualquier causa. Calidad de vida (CV): incluido el resultado funcional, se evaluará según se describe en el capítulo 8. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Proteomics, genomics, and circulating tumour cell analyses of plasma and tumour tissue along the treatment schedule may provide insight in biomarkers associated with response and prognosis. A tissue block (or two-three cores for tissue microarray, TMA) will be collected from the preoperative biopsy (if sufficient material is available) and from the operative specimen. |
| La proteómica, la genómica y el análisis de células tumorales circulantes en el plasma y de tejido tumoral durante todo el tratamiento pueden aportar información sobre los biomarcadores asociados a la respuesta y al pronóstico. Se tomará un bloque (de dos o tres núcleos para análisis de microarrays, TMA) de tejido de la biopsia preoperatoria (si hay suficiente material disponible) y del espécimen operativo |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient visit |
| última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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