Induction Chemotherapy Plus Chemoradiotherapy With or Without Aspirin in High Risk Rectal Cancer

Phase 2

Terminated

• Conditions: Locally Advanced Malignant Neoplasm; Chemoradiation; Rectal Cancer, Adenocarcinoma
• Interventions: Drug: Placebo Oral Tablet; Drug: Aspirin

• Registration Number: NCT03170115
• Lead Sponsor: Instituto Nacional de Cancer, Brazil

Brief Summary

The benefit of aspirin in cancer of the colon and rectum is already known. Recently, it was described its potential activity during chemoradiotherapy, with higher rate of tumor downstaging. Furthermore, induction chemotherapy followed by chemoradiation represents an attractive approach, with more favorable compliance and toxicity profiles. The aim of this study was to evaluate the efficacy of total neoadjuvant treatment and assess the efficacy and feasibility of aspirin use during chemoradiotherapy for high-risk rectal cancer.

Detailed Description

Methods: This is a randomized trial to evaluate induction treatment with XELOX and Capecitabine-based chemoradiotherapy with or without aspirin in a high-risk population selected by MRI. High-risk will be defined by presence of at least one of the following criteria on high-resolution thin-slice MRI (3 mm): tumors extending to within 1 mm of, or beyond the mesorectal fascia; tumor extending 5 mm or more into perirectal fat; resectable cT4 tumors; lower third; nodal involvement; extramural vascular invasion. Random assignment of treatment will be stratified by MRI tumour regression grade. All the patients enrolled in the study will receive XELOX every 21 days for four cycles, unless unacceptable toxicity or progression is detected. After this treatment, patients will be randomized to receive Capecitabine-based chemoradiotherapy with aspirin or placebo (Capecitabine 850 mg/m² 5 days per week combined with radiotherapy with total dose of 50.4 Gy in 28 days). After 8-10 weeks, they will be evaluate by MRI. Patients with incomplete clinical response will be referred to immediate surgery and patients with complete clinical response will be managed with "watch and wait" approach. Patients with progression disease during the treatment phase will be withdrawn from the study and will receive their treatment according to the investigator's judgment.

The sample size was calculated according to Simon's optimal two-stage design. Accordingly, 11 patients must be included in each group during the first stage and 20 during the second stage. A treatment regimen will be considered effective if more than 18 patients of the total 31 show downstaging (final analysis), reaching 80% power with an alpha of 0.05 level of significance.

Study Timeline

• Study First Submitted: 2017-04-17
• Study First Submitted QC: 2017-05-26
• Study First Posted: 2017-05-30
• Study Start: 2017-11-30
• Primary Completion: 2020-01-17
• Study Completion: 2020-01-17
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-14
• Last Update Posted: 2020-12-17

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 25

Inclusion Criteria

1. Histologically confirmed adenocarcinoma of mid or low rectum

2. Locally advanced rectal cancer with one of the high-risk factors confirmed by high-resolution thin-slice Magnetic resonance image (3 mm)

   • tumors extending to within 1 mm of, or beyond the mesorectal fascia;
   • tumor extending 5 mm or more into perirectal fat;
   • resectable cT4 tumors;
   • lower third;
   • nodal involvement;
   • extramural vascular invasion

3. ECOG performance status of 0-2

4. An informed consent has been signed by the patient

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Exclusion Criteria

1. Upper rectal cancer
2. Metastatic disease
3. The patient received any previous therapy for colorectal cancer or another malignancy
4. Other malignant tumours within the last 5 years except cervical carcinoma in situ and basal cell carcinoma of the skin
5. Previous thromboembolic or haemorrhagic events within 6 months prior to registration
6. Patients with malabsorption syndrome or difficulties in swallowing
7. The patient has severe underlying diseases or poor condition to receive chemotherapy or radiotherapy
8. Pregnant of breastfeeding women
9. The patient who participate in another clinical trial, or receives any drug for the trial
10. Uncontrolled peripheral neuropathy (more than grade 2)
11. Active gastrointestinal bleeding

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Oral Tablet	Placebo Oral Tablet	Induction chemotherapy followed by chemoradiotherapy without aspirin Placebo daily during the chemoradiotherapy
Aspirin	Aspirin	Induction chemotherapy followed by chemoradiotherapy with aspirin Aspirin 100mg daily during the chemoradiotherapy

Primary Outcome Measures

Name	Time	Method
Tumor downstaging after induction chemotherapy followed by chemoradiotherapy with or without aspirin	8-10 weeks after chemoradiotherapy	This will be assessed by MR imaging 8-10 weeks after chemoradiotherapy and it will be considered tumor downstaging if mrTRG 1 to 3

Secondary Outcome Measures

Name	Time	Method
Disease-free survival	3 years	defined as the time from surgery to relapse or death, whichever occurred first
Overall survival	5 years	defined as the time from surgery to death, whichever occurred first
Pathologic complete response	8-10 weeks after chemoradiotherapy	it will be defined as the absence of residual invasive cancer on pathological evaluation of the complete resected rectal specimen
Radiological Tumor response rate after induction chemotherapy	3-4 weeks after last induction chemotherapy	This will be assessed by MR imaging after induction chemotherapy
Pathological Tumor response rate	10-12 weeks after chemoradiotherapy	Amount of tumor regression after surgery according to the guideline including Mandard

Trial Locations

Locations (1)

INCA- Instituto Nacional de Câncer; 🇧🇷 Rio de Janeiro, Brazil