Organ Preservation in Locally Advanced Rectal Cancer by Radiochemotherapy Followed by Consolidation Chemotherapy.

Study Overview
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Brief Summary
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There is a growing body of evidence that surgery and associated morbidities can be omitted without compromising oncological safety in selected patients who have achieved a clinical complete response after radiochemotherapy. However with standard neoadjuvant treatment regimens the pathological complete response rate lies in the range between 10%-20%, the number of patients qualifying for non-operative management is even lower since the sensitivity of currently available diagnostic measures for predicting the pathological complete response hardly surpasses 50%-60%.The hereby proposed phase II trial CAO/ARO/AIO-16 aims at finding novel and innovative aspects of rectal cancer treatment. According to recently published data the radiochemotherapy regime in the present study with consolidating chemotherapy and delayed assessment of response has the potential to achieve pathological complete rates of approximately 40%. A standardized re-evaluation after consolidating chemotherapy will select patients who are candidates for organ-preservation. These patients will not undergo radical surgery and will instead be follow-up closely for tumor regrowth.

Official Title
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Organ Preservation in Locally Advanced Rectal Cancer by Radiochemotherapy Followed by Consolidation Chemotherapy. A Prospective Phase II Pilot Trial of the German Rectal Cancer Study Group

Conditions
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Rectal Cancer, Rectal Neoplasms, Rectal Cancer Stage II, Rectal Cancer Stage III

Intervention / Treatment
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* Radiation: Radiotherapy
* Drug: Chemotherapy
* Other: Deep regional hyperthermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients with histologically confirmed diagnosis of rectal cancer localized 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum) Any MRI staged cT3 tumor or any cT1 cN+ or cT2 cN+ with nodal staging according to SOP MRI Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure. Cross-sectional imaging of the abdomen and chest to exclude distant metastases. Aged at least 18 years. No upper age limit. WHO/ECOG Performance Status ≤ 1 Adequate hematological, hepatic, renal and metabolic function parameters Informed consent of the patient Exclusion Criteria: Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy cT4 tumors Positive lateral pelvic lymph nodes Distant metastases (to be excluded by CT scan of the thorax and abdomen) Preexisting fecal incontinence for solid stool Preexisting peripheral sensory neuropathy with functional impairment Preexisting myelosuppression reflected by a neutrophil count < 2.000/mm^3 and/or platelets < 100.000/mm^3 Severe impairment of kidney function with a Creatinin Clearance < 30 ml/min) Prior antineoplastic therapy for rectal cancer Prior radiotherapy of the pelvic region Major surgery within the last 4 weeks prior to inclusion Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment. Subject (male or female) is not willing to use highly effective methods of contraception according to the Clinical trial fertility group On-treatment participation in an interventional clinical study in the period 30 days prior to inclusion Previous or current drug abuse Other concomitant antineoplastic therapy Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder, severe liver function disorders WHO/ECOG Performance Status > 1 Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment. Chronic diarrhea (> grade 1 according NCI CTCAE) Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO stage 0-1), if the patient is continuously disease-free Known allergic reactions on study medication Known dihydropyrimidine dehydrogenase deficiency Medication inhibitors of the dihydropyrimidine dehydrogenase, such as Brivudin, Sorivudin and its analogues. Pernicious anemia or other anemias caused by Vitamin B-12 deficiency. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial). Additionally for hyperthermia cardiac pacemakers and metal implants in the proximity of the pelvis constitute a criterion for exclusion.

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients will undergo different treatments based on response achieved after radiochemotherapy. Clinical Complete Response: Omission of surgery and follow-up Near clinical complete response: Reevaluation in three months Poor / no response: Surgery
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiochemotherapy -> chemotherapy.<br>Radiochemotherapy followed by consolidation chemotherapy. Deep regional hyperthermia can additionally be performed at the centers in Tübingen and Erlangen. | Radiation: Radiotherapy<br>* Radiotherapy: 28 x 1.8 Gy (total: 50.4 Gy), 5 fractions per week on day 1- 38<br>Drug: Chemotherapy<br>* chemoradiotherapy is started according to the following schedule: 5-FU: 250 mg/sqm per day, iv, on day 1-14, day 22-35; Oxaliplatin: 50 mg/sqm, day 1, 8, 22, and 29. After a break of two and a half weeks, patients receive three chemotherapy cycles, starting on day 57, 71 and 85, consisting of: Folinic acid: 400 mg/sqm, 2h-iv; Oxaliplatin: 100 mg/sqm, 2h-iv; 5-FU: 2400 mg/sqm, 46h-iv<br>* Other names: all brands of the used drugs are allowed;Other: Deep regional hyperthermia<br>* Deep regional hyperthermia to the pelvis, total time 90 min, target temperature 41-42°C. Twice weekly, up to a total of 10 sessions within d1 and d38. Deep regional hyperthermia is offered at the centers in Tübingen and Erlangen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response rate | Response to treatment is assessed on day 106 after the start of radiochemotherapy. A clinical complete response is defined by standardized findings in rectoscopy, MRI and digital rectal examination | Day 106 after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local regrowth rate |  | 4 years | 
| Safety of the treatment (toxicity assessment according to NCI CTCAE Version 4.0) |  | 4 years | 
| Fecal incontinence according to Wexner-Vaizey Score | Possible scores range from 0 (perfect continence) to 24 (complete incontinence) | 4 years | 
| Quality of life according to EORTC Quality of Life questionnaire - C30 |  | 4 years | 
| Quality of life according to EORTC Quality of Life questionnaire - CR29 |  | 4 years | 
| Frequency of Low anterior resection syndrome (LARS-scale) |  | 4 years | 
| Surgical morbidity in patients undergoing surgery |  | up to 30 days after surgery | 
| Surgical complications in patients undergoing surgery |  | up to 30 days after surgery | 
| Pathological staging, tumor downstaging (assessed by ypTNM findings in relation to initial cTNM staging), tumor regression grading according to Dworak in patients undergoing surgery |  | Day 123 after the start of treatment | 
| R0 resection rate, rate of circumferential resection margin negativity (> 1mm) in patients undergoing surgery |  | Day 123 after the start of treatment | 
| Rate of sphincter-sparing surgery in patients undergoing surgery |  | Day 123 after the start of treatment | 
| Relapse-free survival (local / distant / overall) |  | 4 years | 
| Overall survival |  | 4 years |