The purpose of the study is to delineate the upstaging percentage of pN0 patients by detection of micrometastases (pN0micro+) and evaluate the benefits from adjuvant chemotherapy on disease recurrence in pN0micro+ CC patients.
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is 3-year DFS in study groups (proportion of patients without
local or distant recurrence, or second primary colorectal cancer, during the
defined period of time).
Secondary outcome
Secondary endpoints are rate of upstaging in pN0 colonic cancer patients
(total number pN0micro+ patients x 100 / total number pN0 colon cancer
patients) and 3-year overall survival.
Background summary
Colorectal cancer is the second most commonly diagnosed malignancy in men and
women in the Netherlands with increasing incidence due to growth and ageing of
the general population. The presence of lymph node metastases remains the most
reliable prognostic predictor and the gold indicator for adjuvant treatment in
colon cancer (CC). Interestingly, in a large percentage of patients without
lymph node metastases in the surgical specimen, who are therefore not subjected
to adjuvant chemotherapy, represent with disease recurrence. In about 10% of
the patients with stage I (Dukes A) and 15-30% with stage II (Dukes B) disease
recurrent locoregional or distant metastases develop within 5 years. One
possible factor could be the presence of occult lymph node metastases at the
time of presentation and surgical resection. Evidence has emerged showing a
significant amount of nodal metastases being smaller than 2 mm or less (<0.2 mm
isolated tumor cells [ITC]; 0.2 - 2mm micrometastasis [MM]) and they are likely
to be missed during conventional gross pathological specimen examination.
Focused examination methods, such as more extensive nodal examination by serial
sectioning or step sectioning, or molecular detection of metastatic nodal cells
by immunohistochemistry (IHC) or reverse transcriptase-polymerase chain
reaction (RT-PCR), increase the likelihood of finding these occult tumour
deposits. However, these focused examination methods are expensive and time
consuming, and therefore not applicable to all lymph nodes derived from the
surgical specimen. By using sentinel lymph node mapping (SLNM) the nodes at
highest risk of harbouring tumour deposits can be potentially detected and more
thoroughly examined. The ex vivo SLNM procedure is technically easy, as the
procedure is executed extracorporally by injection peritumoral blue dye
subserosally or submucosally after which gentle massage of the injection site
is performed. Blue coloured lymph nodes are excised or marked by sutures. The
ex vivo SLNM procedure is characterized by a high accuracy of 90-100%, and
negative predictive value of 80-100%. A rate of 19-57% upstaging is observed.
Current knowledge about the prognostic relevance of nodal micrometastases and
isolated tumor cells has adequately been reviewed in 2004 separately by Iddings
and Nicastri. They concluded that a suggestion of prognostic relevance could be
made for micrometastatic disease related to worsened disease-free survival
(DFS) and overall survival (OS). The meta-analysis performed by Iddings showed
a decreased 3-year DFS and OS of respectively 78% and 78% in pN0micro+ patients
compared to 90% and 97% in pN0micro- patients. A solid conclusion, however,
could not be made because of the lack of well-designed, well powered,
controlled clinical trials. Data from other solid organ malignancies like
breast cancer links micrometastatic disease to a worsened prognosis. Several
prospective trials are currently recruiting. However, an randomized, controlled
clinical trial of significant magnitude is needed to answer this clinically
relevant question.
Adjuvant chemotherapy is only offered to high risk stage I-II colon cancer
patients in the Netherlands at present. Stage I-II CC patients without risk
factors are thought to do not benefit from adjuvant treatment. Individual
randomized trials did not show a survival benefit in stage II colon cancer
patients. The results of meta-analyses and systematic reviews show at the most
a slight disease-free survival benefit of adjuvant chemotherapy in stage II
disease. However, to stress out the importance of further investigation, stage
I-II CC patients do suffer from disease recurrence and their overall 5-year
survival is just around 70-80%. Even stage II CC patients without risk factors
have been shown in several studies to benefit from adjuvant treatment. It is
because of these results that in Eastern countries and the United States stage
II CC patients with or without micrometastatic disease do receive adjuvant
treatment. Thus, there is an international need for better delineation of
high-risk stage I-II CC patients who should be offered adjuvant treatment.
Study objective
The purpose of the study is to delineate the upstaging percentage of pN0
patients by detection of micrometastases (pN0micro+) and evaluate the benefits
from adjuvant chemotherapy on disease recurrence in pN0micro+ CC patients.
Study design
EnRoute+ is an open label, multicenter, randomized controlled clinical trial. A
centrally-performed, computer-generated randomization procedure is instituted.
Eligible patients are randomly assigned at a 1:1 ratio to receive treatment
respectively without or with chemotherapy using block-randomisation per
participating center. Design, flow chart and follow up are presented in Figures
1-3.
Study groups are defined according the randomisation group and pathological
examination result.
group A pN0micro+ with chemotherapy
group B pN0micro+ without chemotherapy
group C pN0micro- without chemotherapy
Intervention
Detection of micrometastases in pN0 colon cancer patients through ex vivo
sentinel lymph node mapping procedure and fine pathology by serial sectioning
and immunohistochemistry. pN0micro+ patients will be randomised to receive
adjuvant chemotherapy or no adjuvant treatment. Adjuvant chemotherapy will be
according to the CAPOX scheme (capecitabine/oxaliplatin) and capecitabine
monotherapy.
Study burden and risks
No additional risks for patients is introduced by the ex vivo SLNM procedure as
the complete procedure is performed extracorporally. Participation in the
randomization study brings risks and discomfort common to adjuvant systemic
chemotherapeutic treatment as given to patients with stage III colon cancer
(CAPOX scheme or capecitabine monotherapy). Dose limiting toxicities of
oxaliplatin/capecitabine include diarrhoea, abdominal pain, nausea, stomatitis
and hand-foot syndrome (hand-foot skin reaction, palmar-plantar
erythrodysesthesia). Most adverse reactions are reversible and do not require
permanent discontinuation of therapy, although doses may need to be withheld or
reduced. A potential negative effect on prognosis can be expected in patients
not receiving adjuvant chemotherapy.
Nieuwstraat 34
5211 NL 's-Hertogenbosch
NL
Nieuwstraat 34
5211 NL 's-Hertogenbosch
NL
Listed location countries
Age
Inclusion criteria
- histological proven colon cancer, clinically localized, judged potentially resectable for cure, without intraoperatively gross nodal involvement
- radiological suspicion of colon cancer, clinically localized, judged potentially resectable for cure, without intraoperatively gross nodal involvement
- patients free of disseminated disease
- written informed consent
Exclusion criteria
- previous chemotherapy
- high risk pN0 patient according to: less then 10 lymph nodes detected in resected specimen, or invasion in other organs (T4NxMx), or colon perforation at presentation, or obstruction at presentation, or angioinvasion at pathological examination.
- clinically positive nodal tumours or advanced disease (stage III / Dukes C)
- haematology (within 7 days before start of chemotherapy treatment): Hb <= 6,2 mmol/l, WBC <= 3,0 x 109/L, platelets <= 100 x 109/L
- renal function (within 7 days before start of chemotherapy treatment): creatinine < 1,25 UL or < 125 µmol/l; creat.clearance < 60 ml/min.(Cockcroft-Gault formula)
- liver function (within 7 days before start of treatment): bilirubin >= 1,5 UL, ASAT >= 2,5 UL, ALAT >= 2,5 UL, gamma-GT >= 2,5 UL, ALP >= 5 UL,
- other current serious illness or medical conditions: severe cardiac illness (NYHA class III-IV) , significant neurologic or psychiatric disorders, uncontrolled infections, active DIC, other serious underlying medical conditions that could impair the ability of the patient to participate in the study
- known hypersensitivity to study drugs
- definite contraindications for the use of corticosteroids
- use of immunosuppressive or antiviral drugs
- any other experimental drugs within a 4-week period prior to start of surgery and adjuvant chemotherapy and throughout the study period
- pregnancy or lactation
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-018612-32-NL |
| CCMO | NL31438.028.10 |