Effect of Concurrent Capecitabine-based Long-term Radiotherapy Followed by XELOX Plus TME in Patients With High Risk Rectal Cancer: a Multi-centers, Randomized Controlled, Open-Label Trial

Rectal Cancer Clinical Trial

— EXPLORE  

Official title:

Effect of Concurrent Capecitabine-based Long-term Radiotherapy Followed by 4 Cycles XELOX Pre- a Delayed TME Compared With 6 Cycles XELOX post-a Regular Timing TME in Patients With High Risk Rectal Cancer: a Multi-centers, Randomized, Open-Label Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03038256
• Other study ID #: 2016-12 EXPLORE
• Status: Recruiting
• Phase: Phase 2
• Start date: January 31, 2018
• Est. completion date: June 1, 2025

Study information

• Verified date: March 2023
• Source: Peking University People's Hospital
• Contact: Yi Wang, MD, PHD
• Phone: 8610-88325813
• Email: wangyi[@]pkuph.edu.cn, jennifer_wy[@]me.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to evaluate the effect of concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX pre- a delayed TME compared with 6 cycles XELOX post- a Regular Timing TME in patients with high-risk rectal cancer defined by MRI.

Description:

This is the randomized controlled, multi-centers, and open-labeled study. Delivering systemic chemotherapy between concurrent capecitabine-based long-term radiotherapy and total mesorectal excision (TME) surgery would be more effectively improved local control rates and improved metastases-free survival rates. The investigators attempted to investigate the effect on pathological response of delivering 4 cycles XELOX between concurrent capecitabine-based long-term radiotherapy and TME with lengthening the interval from radiation to surgery. In this study, the participants with high risk of deeper infiltration, or extramural vessel invasion, or circumferential resection margin involvement, or surrounding organs and structures invaded et al. were recruited. The participants will be randomized (1:1 ratio) to a control and intervention arm. The participants in the control arm will receive best current practice of concurrent capecitabine-based long-term radiotherapy followed by TME and then a 6 cycles of XELOX as standard adjuvant chemotherapy. The participants in the intervention arm will receive concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX as neoadjuvant chemotherapy pre- a delayed TME.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 244
• Est. completion date: June 1, 2025
• Est. primary completion date: April 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Age of 18-75 years;

2. Histologically confirmed adenocarcinoma;

3. The rectal adenocarcinoma 0-12cm from the anal margin on Magnetic resonance imaging (MRI) and/or rigid sigmoidoscopy;

4. High risk of rectal cancer defined by high-resolution MRI: tumor invasion 5mm beyond the muscularis propria, or extramural vascular invasion, or circumferential resection margin unsafe, or the lower rectal cancer invades intersphincteric space, or rectal cancer invades the adjacent structures.

5. Eastern Collaborative Oncology Group performance status score of 0 or 2

6. Able and willing to give informed consent to participate.

Exclusion Criteria:

1. Received preoperative chemoradiotherapy for rectal cancer before the recruitment of this study;

2. Have metastatic disease (including non-regional lymph nodes metastases or resectable liver metastases);

3. Other malignancies, non-adenocarcinoma rectal malignancies or rectal malignancies on the basis of inflammatory bowel disease;

4. Emergency surgery due to bowel obstruction, perforation, bleeding, etc.;

5. Abnormality of capecitabine absorption due to gastrointestinal disease e.g. short bowel syndrome, inflammation bowel disease, et al.;

6. Unresectable concurrent intestinal lesions;

7. Concurrent severe infection;

8. Cardiac Disease:uncontrolled or symptomatic cardiac angina,or uncontrolled arrhythmias and hypertension, or severe congestive heart failure grade II or more based on New York Heart Association (NYHA); myocardial infarction within the past 12 months

9. Peripheral neuropathy more than grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3·0)

10. Bone marrow, liver and kidney function are abnormal e.g., white blood cell = 1.5 × 109 / L; platelet = 100 × 109 / L; Haemoglobin = 80 g/L; Bilirubin > 1.5 times the upper limit; aspartate aminotransferase and alanine aminotransferase > 2.5 times the upper limit; creatinine > 1.5 times the upper limit;

11. Pregnant or lactating women;

12. Life prediction less than 3 months, other severe diseases;

13. Contraindication to MRI; e.g. non-MRI compatible hip prosthesis, cardiac pacemaker;

14. Contraindication to standard chemotherapy including drug interactions and glomerular filtration rate <50 mL/min at baseline;

15. Participators who had been recruited by other clinical trial within three months.

Related Conditions & MeSH terms

• Disease Free Survival
• Pathological Complete Response
• Rectal Cancer
• Rectal Neoplasms

Intervention

Drug:
• concurrent capecitabine-based long-term radiotherapy followed by 4 cycles XELOX and a delayed TME
concurrent capecitabine-based long-term radiotherapy: capecitabine 825mg/m2,bid,d1-5, q week with Radiation treatment. Radiation treatment was given at 1·8 Gy per day, 5 days per week for 5-6 weeks, after a 45 Gy radiation dose in 25 fractions to the pelvis, a boost dose of 5·4 Gy in 3 fractions to the tumor bed or concurrent boosted. XELOX: Oxaliplatin: 130mg/m2,IV,d1; Capecitabine: 1000mg/m2,bid,d1-14; repeated every 3 weeks Surgery Procedure: Total Mesorectal Excision
• concurrent capecitabine-based long-term radiotherapy followed by a Regular TME and 6 Cycles XELOX
concurrent capecitabine-based long-term radiotherapy: capecitabine 825mg/m2,bid,d1-5, q week with Radiation treatment. Radiation treatment was given at 1·8 Gy per day, 5 days per week for 5-6 weeks, after a 45 Gy radiation dose in 25 fractions to the pelvis, a boost dose of 5·4 Gy in 3 fractions to the tumor bed or concurrent boosted. XELOX: Oxaliplatin: 130mg/m2,IV,d1; Capecitabine: 1000mg/m2,bid,d1-14; repeated every 3 weeks Surgery Procedure: Total Mesorectal Excision

Locations

Country	Name	City	State
China	Beijing Friendship Hospital	Beijing	Beijing
China	Peking University People's Hospital	Beijing	Beijing

Sponsors (12)

Lead Sponsor

Collaborator

Peking University People's Hospital

Affiliated Hospital of Hebei University, Beijing Friendship Hospital, Chinese PLA General Hospital, Fujian Medical University Union Hospital, Hebei Medical University Fourth Hospital, Nanfang Hospital of Southern Medical University, Peking Union Medical College Hospital, Peking University Cancer Hospital & Institute, Shanghai Zhongshan Hospital, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Xijing Hospital

Country where clinical trial is conducted

China, 

References & Publications (10)

Chua YJ, Barbachano Y, Cunningham D, Oates JR, Brown G, Wotherspoon A, Tait D, Massey A, Tebbutt NC, Chau I. Neoadjuvant capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision in MRI-defined poor-risk rectal cancer: a phase 2 — View Citation

Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 With or Without Radiation V — View Citation

Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K; Timing of Rectal Cancer Response to Chemoradiation Conso — View Citation

Glynne-Jones R, Anyamene N, Moran B, Harrison M. Neoadjuvant chemotherapy in MRI-staged high-risk rectal cancer in addition to or as an alternative to preoperative chemoradiation? Ann Oncol. 2012 Oct;23(10):2517-2526. doi: 10.1093/annonc/mds010. Epub 2012 — View Citation

Lutz MP, Zalcberg JR, Glynne-Jones R, Ruers T, Ducreux M, Arnold D, Aust D, Brown G, Bujko K, Cunningham C, Evrard S, Folprecht G, Gerard JP, Habr-Gama A, Haustermans K, Holm T, Kuhlmann KF, Lordick F, Mentha G, Moehler M, Nagtegaal ID, Pigazzi A, Pucciar — View Citation

Moran BJ. Predicting the risk and diminishing the consequences of anastomotic leakage after anterior resection for rectal cancer. Acta Chir Iugosl. 2010;57(3):47-50. doi: 10.2298/aci1003047m. — View Citation

Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, — View Citation

Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the Germ — View Citation

Valentini V, van Stiphout RG, Lammering G, Gambacorta MA, Barba MC, Bebenek M, Bonnetain F, Bosset JF, Bujko K, Cionini L, Gerard JP, Rodel C, Sainato A, Sauer R, Minsky BD, Collette L, Lambin P. Nomograms for predicting local recurrence, distant metastas — View Citation

van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 1 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathological complete response rate	Pathological complete response (pCR) rate between control and intervention arm	up to 30days after total mesorectal excision
Secondary	Disease Free Survival	Disease Free Survival was defined as the time from the date of surgery to the date of the local recurrence, and/or distant disease, or tumor-related death.	3-year
Secondary	R0 of total mesorectal excision rate	Overall R0 of total mesorectal excision rate between the control and intervention arm	up to 30days after total mesorectal excision
Secondary	Surgery morbidity	Surgical morbidity reported according to Clavien-Dindo classification	30 days and 12-months
Secondary	quality of surgery	Quality of surgery determined using the mesorectal grading system	Time of surgery