IMRT-SIB and Capecitabine in Preoperative Rectal Cancer Treatment (BISER)

Preoperative Radiochemotherapy With IMRT - Simultaneous Integrated Boost in Locally Advanced Rectal Cancer - BISER

RATIONALE: Using small radiation beamlets of different intensity, IMRT (intensity modulated radiation therapy) allows shaping the dose around planning target volume with better sparing of normal tissue comparing to 3D conformal radiotherapy. It allows daily delivery of higher dose to the tumor with simultaneous integrated boost (SIB), consequently shortening total treatment time with potentially better response to treatment. In advanced rectal adenocarcinoma excellent response to preoperative radiochemotherapy with complete eradication of the primary tumor observed in the histopathological specimen (pathological complete response, pCR) correlates with a favorable overall prognosis, so trying to achieve better response to preoperative treatment with higher pCR seams feasible.

PURPOSE:The hypothesis of this study is that in preoperative radiochemotherapy for locally advanced rectal adenocarcinoma shortening of the total treatment time with IMRT-SIB to 22 daily fractions concomitant with capecitabine results in an improved pCR rate from 9% (Slovenian trial) to 25%. Secondary objectives are to evaluate pathological down-staging rate, histopathological R0 resection rate, sphincter preservation rate, perioperative surgical complication rate, local control, disease-free survival (DFS), overall survival (OS), late toxicity and quality of life.

Study Overview

• Status: Unknown
• Conditions: Rectal Carcinoma
• Intervention / Treatment: Drug: Capecitabine; Procedure: Surgery; Radiation: IMRT-SIB

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • Institute of Oncology
    • Contact: Jasna But-Hadzic, MD; Phone Number: +38615879503; Email: jbut@onko-i.si
    • Contact: Vaneja Velenik, MD,PhD, asist. prof.; Phone Number: +38615879661; Email: vvelenik@onko-i.si
    • Principal Investigator: Jasna But-Hadzic, MD
    • Sub-Investigator: Vaneja Velenik, MD,PhD,asist.prof.
    • Sub-Investigator: Irena Oblak, MD,PhD,asist.prof.
    • Sub-Investigator: Franc Anderluh, MD,MSc
    • Sub-Investigator: Ajra Secerov, MD
    • Sub-Investigator: Ibrahim Edhemovic, MD,MSc
    • Sub-Investigator: Erik Brecelj, MD,PhD
    • Sub-Investigator: Andrej Vogrin, MD
    • Sub-Investigator: Rihard Hudej
    • Sub-Investigator: Mirko Omejc, MD,PhD,prof.
    • Sub-Investigator: Miran Koželj, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Biopsy-proven newly diagnosed primary rectal adenocarcinoma

• Locally advanced tumor fulfilling at least one of the following criteria on pelvic MRI:

  • T ≥ 3 or
  • N ≥ 1
  • Positive mesorectal fascia (MRF), i.e. tumor or lymph node one mm or less from the mesorectal fascia
  • Tumor located od 0 - 15 cm above anocutaneous junction or below peritoneum
• Age 18 years and more
• Signed informed consent
• WHO Performance Status 0-2
• Patients is considered to be mentally and physically ft for chemotherapy as judged by oncologist
• Adequate hematological, hepatic and renal function (WBC ≥ 3.0 x 109/L, neu ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, renal clearance ≥ 50 ml/min, bilirubin ≤ 3x normal value, aspartate transaminase/alanine transaminase (AST/ALT) ≤ 2,5x normal value)

Exclusion Criteria:

• T4 inoperable tumor - extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots
• Metastatic or recurrent rectal cancer
• Other co-existing malignancy or malignancy within the past 5 years, with the exception of adequately treated in situ carcinoma of the cervix or basal cell carcinoma of the skin
• Chronic bowel inflammatory disease
• Pregnant or lactating patient
• Significant heart disease (uncontrolled hypertension despite of medication (> 150/100 mmHg), New York Heart Association (NYHA) class III or IV heart disease,unstable angina or myocardial infarction within the past 1 year prior the study entry, history of significant ventricular arrhythmia requiring treatment)
• Inability to consciously sign the consent form due to physical or psychological disabilities

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: IMRT-SIB	Drug: Capecitabine; Other Names: (Xeloda, Capecitabine Teva, Ecansya); Procedure: Surgery; Other Names: Total Mesorectal Exscision; Radiation: IMRT-SIB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Pathological complete remission rate (pCR)	after the pathological examination of surgical specimens i.e. within 14 days after the operation

Secondary Outcome Measures

Outcome Measure	Time Frame
Toxicity	According to NCI-CTC (version 4.0): every week for 16 week preoperative, perioperative (0-30 days postoperative), early (30 days - 6 months postoperative), and late (more than 6 months postoperative)
Histopathological R0 resection rate	after the pathological examination of resected specimens i.e. within 14 days after the operation
Tumor down-staging rate	after the pathological examination of resected specimens i.e. within 14 days after the operation
Rate of sphincter sparing surgical procedure	Toxicity/safety: one month after surgery.
Loco-regional failure rate	after 3y and 5y of operation
Disease-free survival	after 3y and 5y of operation
Overall survival	after 3y and 5y of the operation
Quality of life	before the treatment, after surgery, after1,2,3,4 and 5 years of the operation

Collaborators and Investigators

• Sponsor: Institute of Oncology Ljubljana

Publications and helpful links

General Publications

• Engels B, De Ridder M, Tournel K, Sermeus A, De Coninck P, Verellen D, Storme GA. Preoperative helical tomotherapy and megavoltage computed tomography for rectal cancer: impact on the irradiated volume of small bowel. Int J Radiat Oncol Biol Phys. 2009 Aug 1;74(5):1476-80. doi: 10.1016/j.ijrobp.2008.10.017. Epub 2009 Feb 21.
• Arbea L, Ramos LI, Martinez-Monge R, Moreno M, Aristu J. Intensity-modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): dosimetric comparison and clinical implications. Radiat Oncol. 2010 Feb 26;5:17. doi: 10.1186/1748-717X-5-17.
• Mok H, Crane CH, Palmer MB, Briere TM, Beddar S, Delclos ME, Krishnan S, Das P. Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma. Radiat Oncol. 2011 Jun 8;6:63. doi: 10.1186/1748-717X-6-63.
• Li JL, Ji JF, Cai Y, Li XF, Li YH, Wu H, Xu B, Dou FY, Li ZY, Bu ZD, Wu AW, Tham IW. Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: a phase II trial. Radiother Oncol. 2012 Jan;102(1):4-9. doi: 10.1016/j.radonc.2011.07.030. Epub 2011 Sep 6.
• Velenik V, Anderluh F, Oblak I, Strojan P, Zakotnik B. Capecitabine as a radiosensitizing agent in neoadjuvant treatment of locally advanced resectable rectal cancer: prospective phase II trial. Croat Med J. 2006 Oct;47(5):693-700.
• Velenik V, Oblak I, Anderluh F. Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer. Radiat Oncol. 2010 Sep 29;5:88. doi: 10.1186/1748-717X-5-88.

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Anticipated): December 1, 2015
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: February 2, 2014
• First Submitted That Met QC Criteria: October 15, 2014
• First Posted (Estimate): October 20, 2014

Study Record Updates

• Last Update Posted (Estimate): October 20, 2014
• Last Update Submitted That Met QC Criteria: October 15, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: IMRT; rectal carcinoma; preoperative radiochemotherapy; SIB
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: 41/12/13