p53 and Response to Preoperative Radiotherapy for T2 and T3

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Rectal Cancer

Intervention / Treatment
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* Radiation: preoperative short course radiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| preoperative short course radiation<br>preoperative short course radiation with 8 weeks delay of surgery | Radiation: preoperative short course radiation<br> <br> |

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| overall survival |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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preoperative short course radiotherapy, delay of surgery, rectal cancer, TP53, predictive marker, MRT imaging