Multicenter, Prospective, RCT：Investigation of Combined Modality Therapy for Locally Advanced Mid/Low Rectal Cancer.

Rectal Cancer, Adenocarcinoma Clinical Trial

Official title:

A Multicenter, Prospective, Randomized Clinical Trial to Investigate the Combined Modality Therapy for Locally Advanced Mid/Low Rectal Cancer.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03042000
• Other study ID #: PUMCH-Colorectal Surgery 02
• Status: Not yet recruiting
• Phase: N/A
• First received: February 2, 2017
• Last updated: February 2, 2017
• Start date: February 2017
• Est. completion date: December 2021

Study information

• Verified date: February 2017
• Source: Peking Union Medical College Hospital
• Contact: Jiaolin Zhou, MD.
• Phone: 8613910136704
• Email: conniezhjl[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

At present, the combined modality treatment of preoperative neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery has become the standard of care for the locally advanced mid/low rectal cancer, having been proved to substantially improve the local control of the disease, whereas not being able to improve the long-term survival. According to present clinical practice guidelines, all patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer are recommended to undergo the preoperative long-term radiotherapy with concurrent 5FU based chemotherapy, followed by the radical resection of the tumor. After surgery, adjuvant chemotherapy (ACT) is recommended for all these patients without considering the postoperative pathological results. Recently, however, some authors proposed that different strategy of combined modality therapy should be applied in different patients according to their risk of relapse, instead of using the uniform NCRT strategy. In this research, on the basis of investigator's previous clinical practice and researches, investigators plan to stratify the patients with cT3-4N0M0 or cTanyN1-2M0 mid/low rectal cancer into several subgroups according to tumor stages and the risk of relapse. Different therapeutic strategy will be applied in different groups, at the aim of improving the overall therapeutic effects, as well as reducing the treatment adverse effects.

This research consists of four trials.

Description:

Trial A: A multicenter, prospective, randomized trial to compare neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery with surgery alone for cT3a-bN0-1aM0 mid rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged T3a-bN0-1aM0 by rectal MRI and/or endorectal ultrasonography (ERUS), the tumor being located 6-12 cm above the anal verge.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: radical surgery + adjuvant chemotherapy (ACT) Group A2: NCRT + radical surgery + ACT

Trial B: A multicenter, prospective, randomized trial to compare combined versus single-agent chemotherapy with concurrent radiotherapy for cT4NanyM0 or cTanyN2M0 rectal cancer.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cT4NanyM0 or cTanyN2M0 by rectal MRI and/or ERUS, or patients with any other risk factors for tumor relapse.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: NCRT with combined chemotherapy (Capox regimen) + radical surgery + ACT Group A2:

NCRT with single-agent chemotherapy (Capecitabine) + radical surgery + ACT

Trial C: A multicenter, prospective, randomized trial to compare transanal ndoscopic microsurgery (TEM) excision versus radical resection of rectal cancer being staged clinical complete response (cCR) after NCRT.

Research objects: Patients with locally advanced rectal cancer, being clinically staged cCR after NCRT.

After giving fully informed consent, the prospective participants will be randomly divided into two groups, receiving the following two treatment modalities.

Group A1: TEM excision + ACT Group A2: radical surgery + ACT

Trial D: A prospective, observational study to determine the value of circulating tumor DNA (ctDNA) for predicting the therapeutic effects of NCRT for locally advanced rectal cancer and the patients' long-term prognosis.

Research objects: Patients with locally advanced mid/low rectal cancer (cT3-4N0M0 or cTanyN+M0) who undergo NCRT.

After giving fully informed consent, the prospective participants will undergo the classical 'NCRT + radical surgery + ACT' comprehensive treatment. Serial analysis of ctDNA will be performed at specific time points including pre-NCRT, post-NCRT, postoperative week 1, post-ACT, postoperative year 1, 2, and 3. The next-generation sequencing of surgical specimens will be performed as well. Participants will be observed and examined during the entire course of treatment and the follow-up period. The pathological results of the surgical specimen and the 3 year disease free survival (3y-DFS) will be the main end-points.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1200
• Est. completion date: December 2021
• Est. primary completion date: December 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

Patients aged 18 to 75 years old. Patients with cT3-4N0M0 or cTanyN+M0 mid/low rectal cancer. Patients with ASA physical status scroe of I to III. Patients who can fully understand the content of the informed consent form and sign it upon their own opinions.

Patients who can coordinate with the researchers to undergo the long-term post-treatment rechecks and follow-ups.

Exclusion Criteria:

Patient has any underlying or current medical condition, which, in the opinion of the Investigator, would interfere with the evaluation of the patient (e.g., end-stage liver disease, pulmonary hypertension, systemic lupus erythematosis etc.).

Patient is pregnant or lactating. Patient has a history of malignancy within 5 years except curatively treated basal cell carcinoma, squamous cell carcinoma in a non-mucosal, ultraviolet exposed area, or cervical carcinoma.

Patient is participating in any other clinical trials within 30 days prior to screening.

Patient has severe mental illness. Patient has any other conditions, which, in the opinion of the Investigator, would interfere with the evaluation of the subject.

Related Conditions & MeSH terms

• Adenocarcinoma
• Neoadjuvant Chemoradiation
• Rectal Cancer, Adenocarcinoma
• Rectal Neoplasms

Intervention

Other:
• non-NCRT
without the preoperative concurrent chemoradiothearpy (no neoadjuvant chemoradiation)
• NCRT
the preoperative concurrent chemoradiothearpy (neoadjuvant chemoradiation)

Drug:
• capecitabine with oxaliplatin
combined chemotherapy with capecitabine with oxaliplatin
• capecitabine
single-agent chemotherapy with capecitabine

Procedure:
• TEM
transanal endoscopic microsurgery (TEM) excision of the lesion
• radical resection
radical resection of rectal cancer

Locations

Country	Name	City	State
n/a

Sponsors (8)

Lead Sponsor	Collaborator
Peking Union Medical College Hospital	Beijing Cancer Hospital, Beijing Chao Yang Hospital, Beijing Friendship Hospital, Beijing Hospital, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Geneplus-Beijing Co. Ltd., People's Hospital of Peking University

References & Publications (11)

Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094. — View Citation

Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, Bardet E, Beny A, Ollier JC, Bolla M, Marchal D, Van Laethem JL, Klein V, Giralt J, Clavère P, Glanzmann C, Cellier P, Collette L; EORTC Radiation Oncology Group.. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014 Feb;15(2):184-90. doi: 10.1016/S1470-2045(13)70599-0. — View Citation

Breugom AJ, Swets M, Bosset JF, Collette L, Sainato A, Cionini L, Glynne-Jones R, Counsell N, Bastiaannet E, van den Broek CB, Liefers GJ, Putter H, van de Velde CJ. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015 Feb;16(2):200-7. doi: 10.1016/S1470-2045(14)71199-4. Review. — View Citation

Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013 Mar 28;368(13):1199-209. doi: 10.1056/NEJMoa1213261. — View Citation

Ferrari L, Fichera A. Neoadjuvant chemoradiation therapy and pathological complete response in rectal cancer. Gastroenterol Rep (Oxf). 2015 Nov;3(4):277-88. doi: 10.1093/gastro/gov039. Review. — View Citation

Jung KU, Kim HC, Park JO, Park YS, Park HC, Choi DH, Cho YB, Yun SH, Lee WY, Chun HK. Adjuvant chemotherapy after neoadjuvant chemoradiation and curative resection for rectal cancer: is it necessary for all patients? J Surg Oncol. 2015 Mar 15;111(4):439-44. doi: 10.1002/jso.23835. — View Citation

Reinert T, Schøler LV, Thomsen R, Tobiasen H, Vang S, Nordentoft I, Lamy P, Kannerup AS, Mortensen FV, Stribolt K, Hamilton-Dutoit S, Nielsen HJ, Laurberg S, Pallisgaard N, Pedersen JS, Ørntoft TF, Andersen CL. Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut. 2016 Apr;65(4):625-34. doi: 10.1136/gutjnl-2014-308859. — View Citation

Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, Silliman N, Tacey M, Wong HL, Christie M, Kosmider S, Skinner I, Wong R, Steel M, Tran B, Desai J, Jones I, Haydon A, Hayes T, Price TJ, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P. Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med. 2016 Jul 6;8(346):346ra92. doi: 10.1126/scitranslmed.aaf6219. — View Citation

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013 Mar 29;339(6127):1546-58. doi: 10.1126/science.1235122. Review. — View Citation

Zhou J, Chang L, Guan Y, Yang L, Xia X, Cui L, Yi X, Lin G. Application of Circulating Tumor DNA as a Non-Invasive Tool for Monitoring the Progression of Colorectal Cancer. PLoS One. 2016 Jul 26;11(7):e0159708. doi: 10.1371/journal.pone.0159708. — View Citation

Zhou J, Qiu H, Lin G, Xiao Y, Wu B, Wu W, Sun X, Lu J, Zhang G, Xu L, Liu Y. Is adjuvant chemotherapy necessary for patients with pathological complete response after neoadjuvant chemoradiotherapy and radical surgery in locally advanced rectal cancer? Long-term analysis of 40 ypCR patients at a single center. Int J Colorectal Dis. 2016 Jun;31(6):1163-8. doi: 10.1007/s00384-016-2579-5. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	3y-DFS	the 3-year disease free survival rate	3 years
Secondary	3y-OS	the 3-year overall survival rate	3 years
Secondary	5y-DFS	the 5-year disease free survival rate	5 years
Secondary	5y-OS	the 5-year overall survival rate	5 years
Secondary	pCR	pathological complete tumor response rate	4 months