Clinical trial NCT03561142: Organ Preservation in Locally Advanced Rectal Cancer by Radiochemotherapy Followed by Consolidation Chemotherapy.
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Rectal Cancer
Rectal Neoplasms
Rectal Cancer Stage II
Rectal Cancer Stage III
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
First posted: 2018-06-19
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients will undergo different treatments based on response achieved after radiochemotherapy.

1. Clinical Complete Response: Omission of surgery and follow-up
2. Near clinical complete response: Reevaluation in three months
3. Poor / no response: Surgery
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Clinical complete response rate
timeFrame: Day 106 after the start of treatment
Secondary outcomes:
measure: Local regrowth rate
timeFrame: 4 years
measure: Safety of the treatment (toxicity assessment according to NCI CTCAE Version 4.0)
timeFrame: 4 years
measure: Fecal incontinence according to Wexner-Vaizey Score
timeFrame: 4 years
measure: Quality of life according to EORTC Quality of Life questionnaire - C30
timeFrame: 4 years
measure: Quality of life according to EORTC Quality of Life questionnaire - CR29
timeFrame: 4 years
measure: Frequency of Low anterior resection syndrome (LARS-scale)
timeFrame: 4 years
measure: Surgical morbidity in patients undergoing surgery
timeFrame: up to 30 days after surgery
measure: Surgical complications in patients undergoing surgery
timeFrame: up to 30 days after surgery
measure: Pathological staging, tumor downstaging (assessed by ypTNM findings in relation to initial cTNM staging), tumor regression grading according to Dworak in patients undergoing surgery
timeFrame: Day 123 after the start of treatment
measure: R0 resection rate, rate of circumferential resection margin negativity (> 1mm) in patients undergoing surgery
timeFrame: Day 123 after the start of treatment
measure: Rate of sphincter-sparing surgery in patients undergoing surgery
timeFrame: Day 123 after the start of treatment
measure: Relapse-free survival (local / distant / overall)
timeFrame: 4 years
measure: Overall survival
timeFrame: 4 years
Other outcomes:
Locations:
city: Erlangen
country: Germany
facility: University Hospital Erlangen
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt
city: Tübingen
country: Germany
facility: University Hospital Tübingen
city: Würzburg
country: Germany
facility: University Hospital Würzburg
Study officials:
affiliation: University Hospital Tübingen
name: Cihan Gani, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gani C, Bonomo P, Zwirner K, Schroeder C, Menegakis A, Rodel C, Zips D. Organ preservation in rectal cancer - Challenges and future strategies. Clin Transl Radiat Oncol. 2017 Mar 23;3:9-15. doi: 10.1016/j.ctro.2017.02.002. eCollection 2017 Apr.
citation: Schroeder C, Gani C, Lamprecht U, von Weyhern CH, Weinmann M, Bamberg M, Berger B. Pathological complete response and sphincter-sparing surgery after neoadjuvant radiochemotherapy with regional hyperthermia for locally advanced rectal cancer compared with radiochemotherapy alone. Int J Hyperthermia. 2012;28(8):707-14. doi: 10.3109/02656736.2012.722263. Epub 2012 Sep 24.
citation: Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, Hofheinz RD, Ghadimi M, Wolff HA, Lang-Welzenbach M, Raab HR, Wittekind C, Strobel P, Staib L, Wilhelm M, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, Liersch T; German Rectal Cancer Study Group. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Aug;16(8):979-89. doi: 10.1016/S1470-2045(15)00159-X. Epub 2015 Jul 15.