JOURNAL ONKOLOGIE – STUDIE

Preoperative FOLFOX Versus Postoperative Risk-adapted Chemotherapy in Patients With Locally Advanced Rectal Cancer

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
September 2020

Letztes Update:
20.11.2023

Wirkstoff:
mFOLFOX (neoadjuvant), XELOX (neoadjuvant), mFOLFOX (adjuvant), XELOX (adjuvant), Capecitabine (adjuvant), infusional 5-FU/FA "AIO" regimen (adjuvant), infusional 5-FU/FA "de Gramont" (adjuvant)

Indikation (Clinical Trials):
Rectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Ralf Hofheinz

Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany), Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest, German Rectal Cancer Study Group,

Studienleiter

Ralf-Dieter Hofheinz, Prof. Dr.
Principal Investigator
Universitätsmedizin Mannheim

Kontakt

Ralf-Dieter Hofheinz, Prof. Dr.
Kontakt:
Phone: +49 621 383
Phone (ext.): 2855
E-Mail: ralf.hofheinz@umm.de» Kontaktdaten anzeigen

Benedict Atzler
Kontakt:
Phone: +49 69 7601
Phone (ext.): 7052
E-Mail: atzler.benedict@ikf-khnw.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Unversity Hospital Mannheim
68167 Mannheim
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Ralf Hofheinz, Prof.
Phone: +49 621 383 2855
E-Mail: Ralf.Hofheinz@umm.de» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

Patients with locally advanced rectal cancer are generally treated with preoperative 5-FU- or

capecitabine-based chemo-radiotherapy (CRT) and total mesorectal excision (TME) surgery in

order to decrease the rate of local failure. In patients with low risk for local failure in

the middle third of the rectum (cT3a/b, N-) as determined with quality controlled MRI, the

German S3 guidelines and the ESMO clinical practice guidelines state that neoadjuvant

radiotherapy may be omitted. However, distant failure rate is still substantial in the range

of 20-25% in these patients highlighting the need for more effective systemic treatment.

The hereby proposed ACO/ARO/AIO-18.2 randomized trial incorporates three novel aspects: (1)

patient selection relies on strict and quality controlled MRI features and therefore

identifies a cohort without imminent need for radiotherapy, (2) the sequence of chemotherapy

and surgery is changed in a way that chemotherapy is administered preoperatively to increase

the rate of patients treated with chemotherapy, and (3) three months of neoadjuvant FOLFOX or

XELOX (instead of up to 6 months adjuvant chemotherapy) are used as a sole perioperative

treatment in order to administer effective doses of the presumably most effective

perioperative treatment at an early time point during the course of disease.

Thus, patients with locally advanced rectal cancer but low risk for local failure (cT1/2N+ in

all thirds of the rectum, cT3a/b N- in the middle third, and cT3-4 Nany in the upper third)

will be included and randomized between three months of neoadjuvant FOLFOX/XELOX in Arm A and

primary resection of the tumor followed by risk (i.e. stage) adapted chemotherapy in Arm B.

Ein-/Ausschlusskriterien

Inclusion Criteria:

1. Male and female patients with histologically confirmed diagnosis of rectal

adenocarcinoma localised 0 - 16 cm from the anocutaneous line as measured by rigid

rectoscopy (i.e. lower, middle and upper third of the rectum), depending on

MRI-defined inclusion criteria (see below).

2. Staging requirements: High-resolution magnetic resonance imaging (MRI) of the pelvis

is the mandatory local staging procedure.

3. Transrectal endoscopic ultrasound (EUS) is used to help discriminate between T1/2 and

early T3 tumors.

4. MRI-defined inclusion criteria:

- Lower third (0-6 cm): cT1/2 with clear cN+ based on MRI-criteria (see SOP in

chapter 13.3 of the appendix), provided CRM- and EMVI- (defined as MRI-EMVI score

0-3; see SOP in chapter 13.3 of the appendix)

- Middle third (≥ 6-12 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; cT3a/b,

i.e. evidence of extramural tumor spread into the mesorectal fat of ≤ 5 mm

provided N-, CRM-, and EMVI-

- Upper third (≥ 12-16 cm): cT1/2 with clear cN+ provided CRM- and EMVI-; any cT3-4

irrespective of nodal status.

5. Spiral-CT of the abdomen and chest to exclude distant metastases.

6. Aged at least 18 years. No upper age limit.

7. WHO/ECOG Performance Status ≤1.

8. Adequate haematological, hepatic, renal and metabolic function parameters:

9. Leukocytes ≥ 3.000/mm³, ANC ≥ 2.000/mm³, platelets ≥ 100.000/mm³, Hb > 9 g/dl

10. Serum creatinine ≤ 1.5 x upper limit of normal

11. Bilirubin ≤ 2.0 mg/dl, SGOT-SGPT, and AP ≤ 3 x upper limit of normal.

12. QTc interval (Bazett**) ≤ 440 ms

13. Informed consent of the patient.

"**" Formula for QTc interval calculation (Bazett): QTc= ((QT) ̅" (ms)" )/√(RR (sec))=

((QT) ̅" (ms)" )/√(60/(frequency (1/min)))

Exclusion Criteria:

1. Distant metastases (to be excluded by CT scan of the thorax and abdomen).

2. Prior antineoplastic therapy for rectal cancer.

3. Prior radiotherapy of the pelvic region.

4. Major surgery within the last 4 weeks prior to inclusion.

5. Subject pregnant or breast feeding, or planning to become pregnant within 6 months

after the end of treatment.

6. Subject (male or female) is not willing to use highly effective*** methods of

contraception during treatment and for 6 months (male or female) after the end of

treatment Male patients treated with Oxaliplatin should take legal advice concerning

sperm conservation before start of therapy and should additionally use a condom during

treatment period. Their female partner of childbearing potential should also use an

appropriate contraceptive measure.

7. On-treatment participation in a clinical study in the period 30 days prior to

inclusion.

8. Previous or current drug abuse.

9. Other concomitant antineoplastic therapy.

10. Serious concurrent diseases, including neurologic or psychiatric disorders (incl.

dementia and uncontrolled seizures), active, uncontrolled infections, active,

disseminated coagulation disorder.

11. Clinically significant cardiovascular disease in (incl. myocardial infarction,

unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac

arrhythmia) ≤ 6 months before enrolment.

12. Chronic diarrhea (> grade 1 according NCI CTCAE).

13. 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.

14. Known allergic reactions or hypersensitivity on study medication or to any of the

other excipients.

15. Evidence of peripheral sensory neuropathy > grade 1 according to CTCAE version 5.0

(see appendix).

16. Severe kidney dysfunction (creatinine clearance < 30 ml/min).

17. Recent or concurrent treatment with brivudine.

18. Pernicious or other megaloblastic anaemia caused by vitamin B12 deficiency.

19. Known dihydropyrimidine dehydrogenase deficiency.

20. 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).

"***"highly effective (i.e. failure rate of <1% per year when used consistently and

correctly) methods: intravaginal and transdermal combined (estrogen and progestogen

containing) hormonal contraception; injectable and implantable progestogen-only hormonal

contraception; intrauterine device (IUD); intrauterine hormone-releasing system (IUS);

bilateral tubal occlusion; vasectomized partner; sexual abstinence (complete abstinence is

defined as refraining from heterosexual intercourse during the entire period of risk

associated with the study treatments).

Studien-Rationale

Primary outcome:

1. disease-free survival (Time Frame - up to 3 years):
time from randomisation to one of the following events: no surgery or non-radical (R2) surgery of the primary tumour, locoregional recurrence after R0/1 resection of the primary tumour, second primary colorectal or other cancer, metastatic disease or progression, or death from any cause, whichever occurred first.

Secondary outcome:

1. Acute and late toxicity (Time Frame - From date of informed consent until the End of Treatment or 30 days after the last dose of study treatment):
assessment of acute and late toxicity according to NCI CTCAE version 5.0

2. Compliance (completion rate) of chemotherapy (Time Frame - From date of randomization until end of chemotherapy, approx. 12 (arm A) respectively up to 34 (arm B) weeks after randomization):
Rate of completion of administered chemotherapy

3. Surgical morbidity and complications (Time Frame - After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization):
Surgical morbidity and complications if surgery is performed and events occur

4. Pathological UICC-staging, including pCR (ypT0N0) rate (Time Frame - After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization):
Pathological staging according UICC criteria, including detailed information about pathologically assessed complete response rate (ypT0N0)

5. R0 resection rate, Negative circumferential resection rate (CRM > 1mm) (Time Frame - After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization):
defined as microscopically margin negative resection with no gross or microscopic tumor remains in the area of the primary tumor and/or samples regional lymph nodes based on evaluation by the local pathologist

6. Tumor regression grading according to Dworak in the experimental arm (Time Frame - After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization):
Grading of tumor regression according to Dworak in the experimental arm

7. Rate of sphincter-sparing surgery (Time Frame - After surgery, approx. 2 (arm B) respectively 20 (arm A) weeks after randomization):
Rate of sphincter-sparing surgery if surgery is performed

8. Rate of W&W with or without local regrowth (Time Frame - Up to 5 years after end of treatment):
Number of performed watch&wait approaches with or without local regrowth compared to planned and performed surgery

9. Cumulative incidence of local and distant recurrences (Time Frame - Up to 5 years after end of treatment):
Total number of local and distant recurrences, if they occur

10. Overall survival (Time Frame - Up to at least 3 years and until 5 years):
Overall survival is defined as the time interval between the date of randomization and the date of death of any cause. Patients who are still alive when last traced will be censored at the date of last follow-up

11. Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-C30 (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months):
Quality of life scores according to validated questionnaires EORTC-QLQ-C30, based on treatment arm, and surgical procedures. 30 questions; score values from 1 (not at all) to 4 (very much) respectively from 1 (very poor) to 7 (excellent). Score outcome depends on score type.

12. Patient reported outcome: Quality of life according to questionnaire EORTC-QLQ-CR29 (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months):
Quality of life scores according to validated questionnaires EORTC-QLQ-CR29, based on treatment arm, and surgical procedures. 29 questions; score values from 1 (not at all) to 4 (very much). Score outcome depends on score type.

13. Patient reported outcome: Functional outcome according to Wexner score (Time Frame - From date of randomization until the date of first documented progression or date of death from any cause, whichever occured first, assessed up to approximately 68 months):
Functional score according to validated Wexner score, based on treatment arm, and surgical procedures. 5 questions; five score values from "never" to "1 per day or more often". The more often the worse the outcome.

Studien-Arme

Experimental: A (experimental arm)
The experimental arm A starts with 6 cycles of mFOLFOX or 4 cycles of XELOX. Surgery is scheduled four or six weeks after day 1 of the last mFOLFOX or XELOX cycle, respectively. No postoperative chemotherapy is planned
Active Comparator: B (control arm)
In the standard arm B, patients undergo surgical resection of the primary tumor followed by stage- (risk-)adapted adjuvant chemotherapy 4-8 weeks after surgery according to recommendations of the S3 guidelines in analogy to colon cancer. Details of the recommended protocols are provided in the protocol.

Geprüfte Regime

mFOLFOX (neoadjuvant) (Folinic acid, Oxaliplatin, 5-FU):
neoadjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
XELOX (neoadjuvant) (Capecitabine, Oxaliplatin):
neoadjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
mFOLFOX (adjuvant) (Folinic acid, Oxaliplatin, 5-FU):
adjuvant application Folinic acid: 400 mg/m2, 2h i.v., on day 1 Oxaliplatin: 85 mg/m2, 2-6h i.v., on day 1 5-FU: 2400 mg/m2, 46-48h i.v., on day 1. Cycles are repeated on day 15. A total of 6 cycles are administered.
XELOX (adjuvant) (Capecitabine, Oxaliplatin):
adjuvant application Capecitabine: 1,000 mg/m2 bid, po, on days 1-14 Oxaliplatin: 130 mg/m2, 2-6h i.v. day 1 Cycles are repeated on day 22. A total of 4 cycles are administered.
Capecitabine (adjuvant) (Capecitabine):
adjuvant application Capecitabine: 1,250 mg/m2 bid, po, on days 1-14 Cycles are repeated on day 22. A total of 8 cycles are administered.
infusional 5-FU/FA "AIO" regimen (adjuvant) (5-FU, Folinic acid):
adjuvant application Folinic acid 2h i.v. 500 mg/m² 5-FU 2,600mg/m² (24h infusion) Days 1, 8, 15, 22, 29, 36; cycle is repeated day 57 (representing one cycle); a total of 3 cycles should be administered.
infusional 5-FU/FA "de Gramont" (adjuvant) (5-FU, Folinic acid):
adjuvant application Folinic acid 2h i.v. 200 mg/m² days 1 and 2 5-FU 400mg/m² bolus followed by 600mg/m² 22h infusion days 1 and 2 The cycle is repeated day 15; a total of 12 cycles should be administered.

Quelle: ClinicalTrials.gov

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