The Clinical Efficacy of Drug Sensitive Neoadjuvant Chemotherapy Based on Organoid Versus Traditional Neoadjuvant Chemotherapy in Advanced Rectal Cancer

A Prospective Multicenter Randomized Controlled Trial of the Clinical Efficacy of Neoadjuvant Therapy Based on Organoids Drug Sensitivity Versus Empirical Neoadjuvant Therapy in the Treatment of Advanced Rectal Cancer

This is a prospective multicenter randomized controlled trial study. According to the enrollment criteria, patients with locally advanced rectal cancer who need neoadjuvant therapy before radical surgery were randomly divided into the organoids drug sensitivity group and the standard whole-course neoadjuvant therapy group. The Organoids drug sensitivity group was treated with personalized neoadjuvant therapy under the guidance of tumor organoids drug sensitivity technology combined with standard long-term radiotherapy. The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience. The tumor pathological complete remission rate (pCR), postoperative complication rate, postoperative tumor withdrawal grade, postoperative recurrence rate, treatment tolerance rate, R0 resection rate, and sphincter preservation rate were observed and compared.

Study Overview

• Status: Not yet recruiting
• Conditions: Neoadjuvant Therapy
• Intervention / Treatment: Drug: standard long-term therapy; Drug: FOLFOX and standard long-term radiotherapy; Drug: FOLFIRI and standard long-term radiotherapy; Drug: 5-FU and standard long-term radiotherapy; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; Drug: Other individualized treatments

Detailed Description

Based on the need for individualized treatment in the era of precision medicine, an in vitro model that can accurately predict the response of patients to treatment is urgently needed, so that suitable patients can receive effective treatment and patients whose treatments are ineffective can avoid adverse reactions. The emergence of tumor organoids technology makes this vision possible.

Tumor-organoid (Patient-Derived Organoids, PDOs) is a kind of micro-organ with a three-dimensional structure, which is cultivated in the environment of 3D matrix glue in vitro. Based on the individualized neoadjuvant therapy based on the drug sensitivity technology of tumor-organoid, the best neoadjuvant therapy can be selected and the clinical efficacy and drug tolerance can be quickly predicted, which is of great significance in the field of accurate tumor therapy. The preliminary study of our group also completed the organ-like library of more than 100 patients with local advanced rectal cancer. It was proved that the organoids of the organoids library had high homology with the original tumor tissue, and the detection period of drug sensitivity of organoids was less than 2 weeks, which was much less than 2 months of PDX drug sensitivity technology in mice, which did not affect the time window of clinical drug treatment, and the results of drug sensitivity were basically consistent with the clinical efficacy.

Therefore, we have reason to believe that tumor organoids chemosensitivity technology, as an economical, high-throughput, and efficient technology for tumor research, is expected to play an important role in clinical individualized treatment of tumors.

Our previous study found that tumor-based organoids drug sensitivity technology can be used as an effective and reliable clinical assistant tool to guide and assist doctors to formulate the best treatment strategy for tumor patients. Personalized neoadjuvant therapy has better clinical efficacy than standard whole-course neoadjuvant therapy.

Therefore, in this study, through a prospective, multicenter, multi-arm umbrella clinical study, patients with locally advanced rectal cancer who need neoadjuvant therapy are randomly divided into two groups: the organoids drug sensitivity group and the standard whole-course neoadjuvant therapy group. To compare the clinical efficacy of personalized neoadjuvant therapy based on tumor organoids chemosensitivity combined with standard long-term radiotherapy with the clinical efficacy of standard whole-course neoadjuvant therapy in locally advanced rectal cancer. This technology can be used in the clinical use of advanced rectal cancer new auxiliary decision-making system so that the standardization of comprehensive treatment of rectal cancer can be implemented in China, which is of great significance for the development of the national economy and the improvement of medical level in China.

• Study Type: Interventional
• Enrollment (Anticipated): 192
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jing Sun, PhD; Phone Number: +86-21-64370045; Email: sj11788@rjh.com.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1) Age: 18-75. 2) qualitative diagnosis: adenocarcinoma was confirmed by enteroscopic biopsy. 3) Localization diagnosis: the tumor is located in the rectum (the distance between the tumor and the anal margin ≤ 12cm).

  4) plain scan of thoracoabdominal pelvis and enhanced CT or MRI evaluation of rectal cancer staging:

The primary tumor invades the muscular layer of the intestinal wall into the surrounding well-known structure, with or without lymph node metastasis in the proper rectal fascia.

b. TNM clinical or pathological stage of tumor: T3-T4N0-2M0. 5) physical condition (ECOG) score ≤ 1. 6) all patients agreed to receive adjuvant chemotherapy for 3 to 6 months after operation.

7) sign informed consent and participate in the project voluntarily.

Exclusion Criteria:

• 1) simultaneous or metachronous multiple primary malignant tumors. 2) preoperative imaging examination or pathological results showed that:

Lateral lymph node metastasis. b. Distant organ metastasis. 3) previous history of malignant tumors. 4) abnormal function of heart, lung, liver, kidney, hematopoiesis and bone marrow reserve, which can not tolerate neoadjuvant therapy and operation.

5) have mental illness or other serious cardiovascular disease. 6) pregnant or lactating women. 7) Emergency surgery (perforation, bleeding, intestinal obstruction, etc.). 8) BRAF mutation was found by gene detection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity
Active Comparator: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity
Active Comparator: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity
Active Comparator: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity
Active Comparator: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity
Active Comparator: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity	Drug: standard long-term therapy; The standard whole-course neoadjuvant therapy group was treated with neoadjuvant simultaneous radiotherapy and chemotherapy (Total Neoadjuvant Therapy, TNT) based on guidelines and clinical experience.; Drug: FOLFOX and standard long-term radiotherapy; FOLFOX and standard long-term radiotherapy based on organoids drug sensitivity; Drug: FOLFIRI and standard long-term radiotherapy; FOLFIRI and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and standard long-term radiotherapy; 5-FU and standard long-term radiotherapy based on organoids drug sensitivity; Drug: 5-FU and pembrolizumab and standard long-term radiotherapy; 5-FU and pembrolizumab and standard long-term radiotherapy based on organoids drug sensitivity; Drug: Other individualized treatments; Other individualized treatments based on organoids drug sensitivity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response	Neoadjuvant therapy and postoperative pathology confirmed that the primary tumor was in complete remission (stage ypT0) and had no residual tumor cells, regardless of whether the regional lymph nodes were involved or not.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative complication	Intra-abdominal bleeding, anastomotic leakage, intra-abdominal infection, intestinal obstruction, postoperative diarrhea, wound infection, pulmonary infection, cardiovascular accident, cerebrovascular accident, etc.	3 years
Tumor Regression Grading	Tumor pathological reaction is graded after neoadjuvant therapy, usually according to the proportion of fibrosis and residual tumor in the tumor. The analytical system for evaluating treatment response recommended by NCCN is as follows: complete response-no living cancer cell residue, moderate reaction-single or small cluster cancer cell residue,mild reaction-residual cancer focus, interstitial fibrosi,adverse reaction-few or no cancer cell regression.	3 years
Local recurrence	Recurrence occurs in the surgical area, with or without the rise of tumor markers. The tumor found in the anastomosis needs to be confirmed by pathological biopsy.	3 years
Distant metastasis	CT or MRI or radionuclide scan can detect metastases in liver, lung and bone, with or without confirmed by pathology.	3 years
Treatment tolerance rate	To evaluate the tolerance and completion of preoperative neoadjuvant therapy.	3 years
R0 resection rate	R0 resection rate of laparoscopic radical surgery for rectal cancer after neoadjuvant therapy.	3 years
anus-saving rate	anus-saving rate after radical resection of rectal cancer after neoadjuvant therapy	3 years

Collaborators and Investigators

• Sponsor: Shanghai Minimally Invasive Surgery Center
• Collaborators: Wuxi Branch of Ruijin Hospital; Shanghai OneTar Biomedicine Co., Ltd.
• Investigators: Principal Investigator: Jing Sun, PhD, Shanghai Minimally Invasive Surgery Center

Publications and helpful links

General Publications

• Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer: An emerging option. Cancer. 2017 May 1;123(9):1497-1506. doi: 10.1002/cncr.30600. Epub 2017 Mar 10.
• Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12. Erratum In: CA Cancer J Clin. 2021 Jul;71(4):359.
• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
• Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009 May 14;459(7244):262-5. doi: 10.1038/nature07935. Epub 2009 Mar 29.
• Cao W, Chen HD, Yu YW, Li N, Chen WQ. Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (Engl). 2021 Mar 17;134(7):783-791. doi: 10.1097/CM9.0000000000001474.
• 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 Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):957-66. doi: 10.1016/S1470-2045(15)00004-2. Epub 2015 Jul 14.
• Shamir ER, Ewald AJ. Three-dimensional organotypic culture: experimental models of mammalian biology and disease. Nat Rev Mol Cell Biol. 2014 Oct;15(10):647-64. doi: 10.1038/nrm3873. Epub 2014 Sep 17.

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: April 22, 2022
• First Submitted That Met QC Criteria: April 22, 2022
• First Posted (Actual): April 28, 2022

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 22, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: neoadjuvant therapy; organoid drug sensitivity; advanced rectal cancer
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Fluorouracil; Pembrolizumab
• Other Study ID Numbers: MISC-WXXR-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No