p53 and Response to Preoperative Radiotherapy for T2 and T3 (PART1)

PART1 - a Prospective Phase II Study to Evaluate the Impact of TP53 Gene Mutations in Patients With Preoperative Radiotherapy for T2 and T3 Rectal Cancer

Background:

Meta-analyses of large randomized trials proved the superiority of preoperative short course radiation and surgery, as compared with surgery alone. Short course radiation results in a 50% reduction in terms of local relapse in stage II and III rectal cancer patients. Patients with complete pathological remission additionally show a significant survival benefit. Complete pathological remission (pCR) occurs in 8% after preoperative radiation and in >16% if the interval between radiation and surgery is at least 8 weeks.

It is generally accepted that mutations in the TP53 gene represent a crucial defect in the apoptosis pathway. Radiation therapy is suggested to act via induction of apoptosis in irradiated cells. Therefore, it is expected that a defect in the TP53 gene has an effect on the success of radiation therapy.

Currently available imaging tools are hardly able to diagnose response to radiation therapy correctly, as this does not essentially correlate with tumor size.

Method:

Aim of this prospective observation study is to strengthen the hypothesis that the TP53 genotype is a promising marker to predict response to radiation therapy in rectal cancer patients. Consequently, the expected results will justify prospective, randomized intervention trials to obtain level of evidence I for the p53 marker hypothesis. Trial endpoint is downstaging and pCR rate. Tumor stage and pathological remission will be evaluated by MRT and pathohistology and correlated to the TP53 genotype of the diagnostic biopsy. Additionally, we will investigate the applicability of novel imaging modalities in magnet resonance tomography to monitor response to radiotherapy.

The objective of this study is

• to evaluate the effect of a genetic tumor marker (TP53 genotype) on the response to preoperative short course radiation (in terms of downstaging and pCR rate)
• to evaluate the applicability of novel magnet resonance tomography imaging modalities to monitor response to preoperative short time radiation.

Conclusion:

The prospective evaluation of the potential predictive marker TP53 may bring us one-step closer to an individualized therapy regimen, which allows the restriction of preoperative radiation in rectal cancer to those patients who will benefit.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Radiation: preoperative short course radiation

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

• Study Contact: Name: Daniela Kandioler, MD; Phone Number: +43 1 40400 56210; Email: daniela.kandioler@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna, Department of Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Rectal cancer patients with clinical staging T2/T3 Nx M0

Description

Inclusion Criteria:

Patients who are eligible for this observational study will be treated according to current standards with preoperative short course radiation (5x5 Gy) and a subsequent interval to surgery of at least 8 to maximum 16 weeks.

According to standards of rectal cancer therapy, eligible patients will meet the following criteria:

• Histologically confirmed adenocarcinoma of the rectum
• Tumor staging with MRI
• Inferior margin of the tumor located not farther than 15 cm from anal verge and below the level of S1-2
• Tumor stage T2 and T3
• No evidence of metastatic disease
• No prior tumor therapy for rectal or pelvic cancers (surgery, radio-, chemo-, immunotherapy, molecular target therapy, or any other type of tumor therapy)
• Medical fitness of the patient for treatment (decided by the involved physician)
• Patient compliance
• Signed informed consent from the patient or a legal representative, for the analysis of the tumor including genetic analyses of the tumor DNA.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons

• Clinical stage T1 (appropriate for local excision),
• Clinical stage T4 (Radio/Chemotherapy)
• Clinical stage M+ (distant metastases)
• No tumor staging with MRI
• Inoperability (technical or functional)
• Prior tumor therapy of the pelvis
• Concurrent administration of any other tumor therapy
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment
• Serious concomitant disorders or attitudes of the patient that would compromise the safety of the patient or his/her ability to complete the study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
preoperative short course radiation; preoperative short course radiation with 8 weeks delay of surgery	Radiation: preoperative short course radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Interaction between the status of the biomarker TP53 and response to treatment	Primary outcome measure is the interaction between the status of the biomarker TP53 and response to radiation. The TP53 maker status is determined by standardized gene specific sequencing of the TP53 using DNA from formalin fixed paraffin embedded material from diagnostic biopsies. Response to treatment is determined by "down sizing" - down sizing will be measured by comparison of pretreatment T stage with pathohistological post treatment T stage . Pretreatement T stage is assessed with MRI, and supported by endosonography. Posttreatment T stage will be assessed prior to operation with MRI and after resection in the pathohistological specimen. The postreatment MRI results will be compared pathohistology.	weeks 12-16 after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival		3 years
pCR rate	pCR - pathohistological complete resmission as assessed in surgical specimen	12-16 weeks after treatment
complete resection rate	Patholohistological assessment	12-16 weeks after treatment
relapse	local and distant relapse	3 years

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Study Chair: Daniela Kandioler, MD, MUW

Publications and helpful links

General Publications

• Kandioler D, Zwrtek R, Ludwig C, Janschek E, Ploner M, Hofbauer F, Kuhrer I, Kappel S, Wrba F, Horvath M, Karner J, Renner K, Bergmann M, Karner-Hanusch J, Potter R, Jakesz R, Teleky B, Herbst F. TP53 genotype but not p53 immunohistochemical result predicts response to preoperative short-term radiotherapy in rectal cancer. Ann Surg. 2002 Apr;235(4):493-8. doi: 10.1097/00000658-200204000-00006.

Helpful Links

• Homepage of the p53-research group

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Anticipated): December 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: May 14, 2014
• First Posted (Estimate): May 16, 2014

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: April 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: rectal cancer; TP53; preoperative short course radiotherapy; delay of surgery; predictive marker; MRT imaging
• 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
• Other Study ID Numbers: PART1