Rectal Preserving Treatment for Early Rectal Cancer. A Multi-centred Randomised Trial of Radical Surgery Versus Adjuvant Chemoradiotherapy After Local Excision for Early Rectal Cancers (TESAR)

• ClinicalTrials.gov Identifier: NCT02371304
• Recruitment Status: Recruiting
• First Posted: February 25, 2015
• Last Update Posted: September 12, 2017
• Sponsor: VU University Medical Center
• Information provided by (Responsible Party): Jurriaan B. Tuynman, VU University Medical Center

Study Description

Brief Summary:

Current therapy for early colorectal cancer is radical Total Mesorectal Excision (TME). Colorectal surgical resections are accompanied with high morbidity of up to 33% and 90 days mortality of up to 9% in the fragile elderly patients as is seen in the results of the Dutch Surgical Colorectal Audit (DSCA) of 2013. Additionally, rectal cancer surgery is associated with substantial loss of health related quality of life due to defecation disorders, incontinence, sexual dysfunction and stoma related morbidity. These disadvantages are acceptable when radical surgery is the only option for cure. Advances in technology enabled the development of local excision of early rectal cancer with precise endoluminal microsurgery or local endoscopic excision resulting in a significant decrease in short- and long term morbidity. However current evidence is of inadequate quality to conclude on the oncologic safety of local treatment for early rectal cancer. Imaging can predict outcome and tailors treatment in more advanced cancer but fails in early cancer. Pathological assessment of the excised tumor tissue provides the optimal information on tumor stage, tumor characteristics and tumor differentiation, thereby it enables to predict the risk of recurrence after local treatment alone. For early rectal cancers, with a low risk on recurrence based on favourable tumor characteristics local excision is seen as safe and these patients do not require an additional treatment. However, for patients with early rectal cancer with a higher risk on recurrence based on tumor characteristics there is no consensus on the additional treatment after local excision. According to the National guideline these patients receive a TME procedure. However, for this subgroup of patients local treatment followed by chemoradiotherapy might also be oncological safe. Current evidence is of inadequate quality to be conclusive. For this subgroup of patients with early rectal cancer with high risk tumorcharacteristics the TESAR trial is designed, in which patiens will be randomised after local endoluminal excision between an additional TME-procedure (standard) and adjuvant chemoradiotherapy. Primary endpoint of the study will be local recurrence at 3 three year follow-up.

Condition or disease	Intervention/treatment	Phase
Rectal Cancer	Radiation: Adjuvant chemoradiotherapy; Procedure: Additional TME surgery; Drug: capecitabine	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Rectal Preserving Treatment for Early Rectal Cancer. A Multi-centred Randomised Trial of Radical Surgery Versus Adjuvant Chemoradiotherapy After Local Excision for Early Rectal Cancers
• Study Start Date: October 2015
• Estimated Primary Completion Date: June 2022
• Estimated Study Completion Date: January 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Total Mesorectal Excision; After local excision patients will receive additional TME surgery	Procedure: Additional TME surgery
Experimental: Adjuvant chemoradiotherapy; After local excision. Patients will receive capecitabine 825 mg/m2 twice a day for 5 weeks only on weekdays. This will be combined with 1.8 Gy in 25 fractions with a limited dose only on the mesorectum	Radiation: Adjuvant chemoradiotherapy; Patients will receive capecitabine 825 mg/m2 twice a day for 5 weeks only on weekdays. This will be combined with 1.8 Gy in 25 fractions with a limited dose only on the mesorectum; Drug: capecitabine

Outcome Measures

Primary Outcome Measures :

1. Recurrence free at 3 year follow-up [ Time Frame: 3 year ]

Secondary Outcome Measures :

1. Treatment related morbidity [ Time Frame: 1,3 and 5 year follow-up ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient has had a margin free (no carcinoma in resection margin) endoluminal local excision (by TEM, TAMIS, TSPM, EMR/ESD or polypectomy) of an early rectal cancer (below 10 cm).
2. Only lesions for which TME surgery is indicated can be included (If a partial mesorectal excision (PME) is indicated the patient should be excluded).
3. Pathological confirmation of the rectal adenocarcinoma fulfilling the following criteria: T1 with size 3-5 cm or pT1, maximum size 3 cm, with at least poor differentiation and/or lymphatic and/or venous invasion and/or SM3 invasion
4. Pathological confirmation of the rectal adenocarcinoma fulfilling the following criteria: pT2, maximum size 3 cm, well differentiated and without lymphatic or venous invasion.
5. Complete colonoscopy, without synchronous colorectal cancer
6. cN0 stage based on pelvic MRI; lymph nodes smaller than 10 mm will be considered as benign, independent of morphologic features. Staging done within 6 weeks before randomisation.
7. Adequate distant staging (CT-thorax abdomen) without signs of distant metastasis (cM0)
8. Male or female, Age > 18 years.
9. Life expectancy of at least 12 months.
10. Medically fit (WHO 0-2) to undergo radical surgery and/or radiation.

11. No contraindications to chemotherapy, including adequate blood counts;

    • white blood count >= 4.0 x 10 9/l
    • platelet count >=100 x 109/l
    • clinical acceptable haemoglobin levels
    • bilirubin < 35 umol/l
    • creatinine levels indicating renal clearance of >=50 ml/min
12. The patient is willing and able to comply with the protocol for the duration of the study, and scheduled follow-up visits and examinations.
13. Written (signed and dated) informed consent and be capable of co-operating with protocol.

Exclusion Criteria:

1. Incomplete or inconclusive resection margin (less than 1mm clearance from the local excision margin or specimens with uncertain deep margin).
2. T1 tumour < 3 cm, moderate/well differentiated, without venous or lymphatic or SM3 invasion.
3. T1 tumour >5 cm and T2 tumour > 3 cm
4. Presence of metastatic disease or recurrent rectal tumour.
5. Previous pelvic radiation
6. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment.
7. 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.
8. Pregnancy, breast-feeding or fertile women without active birth control
9. Clinically significant (i.e. active) cardiovascular disease for example cerebro vascular accidents (<6 months prior to randomization), myocardial infarction (<6 months prior to randomization), unstable angina, New York Heart Association (NYHA) grade II or higher, congestive heart failure, serious cardiac arrhythmia requiring medication.
10. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
11. History of severe and unexpected reactions to fluoropyrimidine therapy
12. Hypersensitivity to capecitabine.
13. Patients with severe leukopenia, neutropenia, or thrombocytopenia.
14. Patients with severe hepatic impairment. 15. Patients with severe renal impairment (creatinine clearance below 30 ml/min).

16. Medical or psychiatric conditions that compromise the patient's ability to give informed consent.

17. Patients known with dihydropyrimidine dehydrogenase deficiency 18. Any contra-indications to undergo MRI imaging.

Contacts and Locations

Contacts

Contact: Thomas Koedam; t.koedam@vumc.nl

Contact: Jurriaan Tuynman; j.tuynman@vumc.nl

Locations

Netherlands

VU University Medical Center; Recruiting

Amsterdam, Netherlands

Contact: J.B. Tuynman, surgeon

Sponsors and Collaborators

VU University Medical Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Borstlap WA, Tanis PJ, Koedam TW, Marijnen CA, Cunningham C, Dekker E, van Leerdam ME, Meijer G, van Grieken N, Nagtegaal ID, Punt CJ, Dijkgraaf MG, De Wilt JH, Beets G, de Graaf EJ, van Geloven AA, Gerhards MF, van Westreenen HL, van de Ven AW, van Duijvendijk P, de Hingh IH, Leijtens JW, Sietses C, Spillenaar-Bilgen EJ, Vuylsteke RJ, Hoff C, Burger JW, van Grevenstein WM, Pronk A, Bosker RJ, Prins H, Smits AB, Bruin S, Zimmerman DD, Stassen LP, Dunker MS, Westerterp M, Coene PP, Stoot J, Bemelman WA, Tuynman JB. A multi-centred randomised trial of radical surgery versus adjuvant chemoradiotherapy after local excision for early rectal cancer. BMC Cancer. 2016 Jul 21;16:513. doi: 10.1186/s12885-016-2557-x.

• Responsible Party: Jurriaan B. Tuynman, MD, PhD, VU University Medical Center
• ClinicalTrials.gov Identifier: NCT02371304 History of Changes
• Other Study ID Numbers: NL50364.029
• First Posted: February 25, 2015
• Last Update Posted: September 12, 2017
• Last Verified: September 2017

Keywords provided by Jurriaan B. Tuynman, VU University Medical Center:

local therapy; adjuvant chemoradiotherapy; rectal preserving

Additional relevant MeSH terms:

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Capecitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents