Short-course Radiotherapy (5×6Gy/7Gy/8Gy) Followed by Neo-adjuvant Chemotherapy for Locally Advanced Rectal Cancer

February 14, 2023 updated by: Benhua Xu, Fujian Medical University Union Hospital

Phase I Trial of Dose-escalation Preoperative Short-course Radiotherapy (5×6Gy/7Gy/8Gy) Followed by Neo-adjuvant Chemotherapy in Locally Advanced Rectal Cancer : the FJUHR-01 Trial

Preoperative radiotherapy followed by total mesorectal excision (TME) has been recommended as the preferred treatment method for locally advanced rectal cancer. Similar rates of local control, survival and toxicity were observed in preoperative long-course radiotherapy (LCRT) (45-50.4 Gy in 25-28 fractions) and short-course radiotherapy (SCRT) of 25 Gy in five fractions. For the convenience of SCRT, a growing number of patients tend to receive SCRT as preoperative radiotherapy. Although SCRT can shorten treatment interval and cut down the cost of treatment, it's pathological complete response (pCR) rate is relatively low (SCRT vs. LCRT: 0.7% vs. 16%). Hence, the optimal pattern of preoperative therapy of locally advanced rectal cancer still deserves to be explored. Previous studies have confirmed the feasibility and safety of 30Gy/5 fractions in SCRT of rectal cancer and verified that SCRT followed by mFOLFOX6 chemotherapy can improve the pCR rates. Therefore, investigators aimed to establish a dose escalation mode of SCRT (5×6Gy/7Gy/8Gy) followed by four cycles of modified FOLFOX6(mFOLFOX6) chemotherapy to test the safety and efficacy in treating locally advanced rectal cancer.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rectal cancer is one of the most common malignant tumors in western countries and its incidence and mortality rates have been ascending for several decades in our country. Surgical resection is the primary treatment method for resectable tumor. Post-operative chemo-radiotherapy can improve local control but can also lower the tolerance rate and increase the incidence of postoperative complications. It is generally not recommended as a regular treatment method excepting the patients who have high risk factors of recurrence after surgery. Preoperative radiotherapy followed by total mesorectal excision(TME) has been recommended as a preferred treatment regimen for locally advanced rectal cancer for it is more effective in local control compared with that of postoperative radiotherapy. The traditional long-course radiotherapy(LCRT) is 45-50.4 Gy in 25-28 daily fractions given with concurrent chemotherapy and delayed surgery(4-8 weeks after chemo-radiotherapy). Also considered an alternative treatment option is preoperative short-course radiotherapy(SCRT) of 25 Gy in five daily fractions and followed by immediate surgery(1 week after SCRT). Similar rates of local control, survival and toxicity were observed in these two regimens. Although SCRT can reduce treatment interval and cut down costs, it's pathological complete response(pCR) rates are relatively low. Bujko et al. reported that the pCR rate for LCRT and SCRT are 16% and 0.7%, respectively. This difference may partially related to the interval between preoperative radiotherapy and surgery. The pCR rates are higher in patients who have the longer interval. In the latest multicenter, randomized, non-blinded, phase III, non-inferiority trial(Stockholm III), participants were randomly assigned to receive either 5×5 Gy radiation dose with immediate surgery within 1 week(SCRT) or after 4-8 weeks(SCRT with delay) or 25×2 Gy radiation dose followed by surgery after 4-8 weeks(LCRT with delay). All these regimens show similar oncological results. However, LCRT with delay prolongs the treatment interval substantially. Although radiation-induced toxicity was observed after SCRT with delay, postoperative complications were significantly reduced compared with that of SCRT followed by immediate surgery. Thus, SCRT with delay to surgery is a useful alternative to conventional SCRT with immediate surgery.

The optimal pattern of dose fractionation of preoperative radiotherapy still deserves to be explored. J Widder et al. reported that SCRT of 25 Gy administered within 1 week of 2.5 Gy twice daily for resectable rectal cancer generates a well-tolerated and simple way to increase local control. A prospective phase II study of SCRT for rectal cancer with twice daily fractions of 2.9 Gy to a total dose of 29 Gy also results in tolerable toxicity and favourable local control. Although both of the modifications of SCRT have acceptable toxicity and well local control, the improvement in overall survival is still limited. Investigators suppose that whether escalating single radiation dose of SCRT (6Gy,7Gy,8Gy...) may further improve local control and overall survival with tolerable toxicity. A prospective phase II study of SCRT that made a boost to the gross tumor volume(GTV) up to a total of 30 Gy in five fractions to investigate the feasibility and the rate of complete pathological response. The results demonstrated that acceptable toxicity and a better rate of pCR can be achieved. Studies have confirmed that high pCR rates were beneficial to survival. Hence, investigators consider that it is feasible to escalate single radiation dose of SCRT in treating rectal cancer. The theoretical basis of escalation of single radiation dose of SCRT may improve survival outcome are as follows:

  1. To improve the biological equivalent doses(BED) of the tumor Biological equivalent doses (BED) were used for comparison of various fractionations of radiotherapy and were calculated with the formula for late normal tissue toxicity BED (Gy) =nd[1 +(d /α / β)] n: number of fractions d: single fraction dose (Gy) α/β: take 3 Gy for normal tissues According to the formula, BED is determined by n, d and α/β. This suggests that escalation of fractional dose can significantly increase BED of tumor, thus can amount to the greater kill to tumor cells.
  2. To induce tumor immune response Several studies reported that radiotherapy can induce or regulate immune response, which can suppress tumor growth and generate inflammatory response. Field radiotherapy can motivate the radiation effects of local-regional and distant area of the body.

The other one criticism in treating rectal cancer is distant metastasis that hinder the improve of overall survival. Preoperative chemotherapy can play a role in controlling the potential micrometastases. Previous studies have confirmed that SCRT followed by mFOLFOX6 chemotherapy can improve the pCR rates. Therefore, in this Phase I Study, the safety and efficacy will be tested using a dose escalation mode of SCRT (5×6Gy/7Gy/8Gy) followed by four cycles of mFOLFOX6 chemotherapy when treating locally advanced rectal cancer.

Dose Escalation Methods in Phase I Cancer Clinical Trials:

Three patients receive the lowest level of radiation dose in a cohort and dose limited toxicity(DLT) is observed. If none of the patients show DLT, another cohort of three patients receive the next higher level of dose. If not, a further cohort of three patients will receive the same dose when one or more patients exhibit DLT. Of the six patients treated at this dose level, the trial continues at the next dose level if only one out the six patients appears DLT and stops at that dose level if at least two patients appear DLT. When the escalation stopped, additional three patients will be required at this dose level. The maximum sample size will depend on the dose level that is in progress.

Study Type

Observational

Enrollment (Anticipated)

9

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Fujian
      • Fuzhou, Fujian, China, 350000
        • Recruiting
        • Fujian Medical University Union Hospital
        • Contact:
          • Benhua Xu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Hosptal in-patients

Description

Inclusion Criteria:

  • Previously untreated, biopsy-proven stage T3-4 and/or N+，resectable rectal adenocarcinoma with the tumors near anal verge within 12 cm;
  • Male or non-pregnant female;
  • Between 18 and 70 years of age;
  • Adequate hematologic function: white blood cell(WBC) counts≥4,000/mm3, neutrophils counts ≥ 1,500/mm3, platelet counts ≥ 100,000/µL, hemoglobin ≥ 9g/L;
  • Adequate renal function: creatinine ≤ 1.5×upper normal limit;
  • Adequate hepatic function: total bilirubin, glutamic oxalacetic transaminase, glutamate pyruvate transaminase level < 2.0×upper normal limit);
  • Satisfactory performance status: Karnofsky Performance Status(KPS)≥70;
  • Approval from the ethics committee and prior written informed consents from all patients before registration were obtained.

Exclusion Criteria:

  • the evidence of relapse or distant metastasis;
  • receiving treatment of other anti-cancer drugs or methods;
  • Patients have low compliance and are not able to complete the entire trial;
  • the presence of uncontrolled life-threatening diseases;
  • dysfunction of heart, brain, lung and et al.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Group 1
preoperative short-course radiotherapy(5×6Gy) followed by 4×mFOLFOX6 chemotherapy
Radiation: preoperative short-course radiotherapy
Patients will be enrolled into Group 1 to 3 according to the time order of entering the study to receive dose from 6Gy×5F to 8Gy×5F using the traditional 3+3 dose escalation design.
Other Names:
  • 4 cycles mFOLFOX6 chemotherapy
Group 2
preoperative short-course radiotherapy(5×7Gy) followed by 4×mFOLFOX6 chemotherapy
Radiation: preoperative short-course radiotherapy
Patients will be enrolled into Group 1 to 3 according to the time order of entering the study to receive dose from 6Gy×5F to 8Gy×5F using the traditional 3+3 dose escalation design.
Other Names:
  • 4 cycles mFOLFOX6 chemotherapy
Group 3
preoperative short-course radiotherapy(5×8Gy) followed by 4×mFOLFOX6 chemotherapy
Radiation: preoperative short-course radiotherapy
Patients will be enrolled into Group 1 to 3 according to the time order of entering the study to receive dose from 6Gy×5F to 8Gy×5F using the traditional 3+3 dose escalation design.
Other Names:
  • 4 cycles mFOLFOX6 chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological complete response(pCR) rate
Time Frame: four weeks after surgery
According to pathological response criteria, a total regression is considered a complete response.
four weeks after surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of acute toxicities during radiation or chemotherapy
Time Frame: three months
Number of participants with abnormal laboratory values and/or adverse events that are related to radiation or chemotherapy as assessed by Common Toxicity Criteria for Adverse Effects(CTCAE) v4.0.
three months
R0 resection rate
Time Frame: four weeks after surgery
According to the pathological outcomes after received surgery.
four weeks after surgery
Sphincter preservation rate
Time Frame: four weeks after surgery
According to the pathological outcomes after received surgery.
four weeks after surgery
Incidence of surgical complications
Time Frame: four weeks after surgery
Surgical complications are defined as those occurring within 30 days after surgery, such as re-operation, anastomotic fistula, bleeding, infection and death related to the operation.
four weeks after surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fujian Medical University Union Hospital

Investigators

  • Principal Investigator: Benhua Xu, Fujian Medical University Union Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 1, 2022

Primary Completion (Anticipated)

June 1, 2025

Study Completion (Anticipated)

December 1, 2026

Study Registration Dates

First Submitted

February 28, 2018

First Submitted That Met QC Criteria

March 8, 2018

First Posted (Actual)

March 15, 2018

Study Record Updates

Last Update Posted (Actual)

February 16, 2023

Last Update Submitted That Met QC Criteria

February 14, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FujianUnionH

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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