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The purpose of this study is to identify the most promising treatment sequence in total neoadjuvant therapy for locally advanced rectal cancer with a high risk of recurrence.
International recommendations for the treatment of locally advanced rectal cancer with a high risk of disease recurrence are inconsistent regarding the optimal sequence of total neoadjuvant therapy. In a German randomized study, a higher rate of pathological complete response was observed with consolidation chemotherapy.
This study compares induction chemotherapy followed by chemoradiotherapy and consolidation chemotherapy with chemoradiotherapy followed by consolidation chemotherapy in patients with locally advanced rectal cancer and high-risk features for recurrence.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| consolidation chemotherapy | Experimental | chemoradiation: intensity-modulated irradiation technique with simultaneous integrated boost to the tumor (IMRT-SIB) or with volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (VMAT-SIB) to the total tumor dose of 46.2 Gy in T1-3 tumors and 48.4 Gy in T4 tumors in 22 fractions with concomitant chemotherapy (CT) with capecitabine (dosage: 825 mg / m2 / 12 h per os continuously from the first to the last day of irradiation). 6 cycles of capecitabine and oxaliplatin (CAPOX) chemotherapy. One cycle of CAPOX CT lasts 3 weeks and consists of capecitabine 1000 mg / m2 / 12h per os for 1-14 days and oxaliplatin 130 mg / m2 intravenously in a two-hour infusion on day 1. |
|
| induction chemotherapy | Active Comparator | 4 cycles of induction CAPOX chemotherapy. One cycle of CAPOX CT lasts 3 weeks and consists of capecitabine 1000 mg / m2 / 12h per os for 1-14 days and oxaliplatin 130 mg / m2 intravenously in a two-hour infusion on day 1. Chemoradiation: intensity-modulated irradiation technique with simultaneous integrated boost to the tumor (IMRT-SIB) or with volumetric modulated arc therapy (VMAT) with simultaneous integrated boost (VMAT-SIB) to the total tumor dose of 46.2 Gy in T1-3 tumors and 48.4 Gy in T4 tumors in 22 fractions with concomitant CT with capecitabine (dosage: 825 mg / m2 / 12 h per os continuously from the first to the last day of irradiation). 2 cycles of consolidation CAPOX chemotherapy. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Consolidation CAPOX Chemotherapy | Drug | Six cycles of CAPOX chemotherapy are administered after chemoradiotherapy. CAPOX consists of capecitabine and oxaliplatin according to the study protocol. |
| Measure | Description | Time Frame |
|---|---|---|
| complete remission rate | The proportion of complete responses will be defined as the sum of the proportions of pCR in operated patients and cCR in non-operated patients. | 2 weeks after completion of TNT |
| Measure | Description | Time Frame |
|---|---|---|
| Overall survival | time from randomization to death | after 3 years of follow-up |
| Survival without recurrence of the disease | time from the end of treatment (in case of cCR) or from radical surgery to death or recurrence of the disease - whichever comes first. |
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Inclusion Criteria:- histologically proven rectal adenocarcinoma
no distant metastases on CT scan (M0 disease)
at least one high risk factor for disease recurrence identified on magnetic resonance imaging (MRI):
capacity for informed consent
willingness to attend regular check-ups during and after treatment
Exclusion Criteria:history of previous irradiation in the pelvic area
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| Name | Affiliation | Role |
|---|---|---|
| Vaneja Velenik, PD | Institute of Oncology Ljubljana | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Institute of Oncology | Ljubljana | Slovenia | 1000 | Slovenia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24717570 | Background | Cercek A, Goodman KA, Hajj C, Weisberger E, Segal NH, Reidy-Lagunes DL, Stadler ZK, Wu AJ, Weiser MR, Paty PB, Guillem JG, Nash GM, Temple LK, Garcia-Aguilar J, Saltz LB. Neoadjuvant chemotherapy first, followed by chemoradiation and then surgery, in the management of locally advanced rectal cancer. J Natl Compr Canc Netw. 2014 Apr;12(4):513-9. doi: 10.6004/jnccn.2014.0056. | |
| 33643528 |
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Participants are randomized to one of two treatment sequences of total neoadjuvant therapy: induction chemotherapy followed by chemoradiotherapy and consolidation chemotherapy, or chemoradiotherapy followed by consolidation chemotherapy.
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| Induction CAPOX Chemotherapy | Drug | Four cycles of CAPOX chemotherapy are administered before chemoradiotherapy, followed by two cycles of CAPOX chemotherapy after chemoradiotherapy. CAPOX consists of capecitabine and oxaliplatin according to the study protocol. |
|
| after 3 years of follow-up |
| Disease free survival | the time from the end of treatment (in the case of cCR) or surgery to the recurrence of disease, the onset of new cancer, death from cancer or other causes | after 3 years of follow-up |
| local control | the time from the end of the treatment (in the case of cCR) or surgery to local recurrence | after 3 years of follow-up |
| Background |
| Tuta M, Boc N, Brecelj E, Peternel M, Velenik V. Total neoadjuvant therapy vs standard therapy of locally advanced rectal cancer with high-risk factors for failure. World J Gastrointest Oncol. 2021 Feb 15;13(2):119-130. doi: 10.4251/wjgo.v13.i2.119. |
| 31652124 | Background | Tuta M, Boc N, Brecelj E, Omejc M, Anderluh F, Ermenc AS, Peressutti AJ, Oblak I, Krebs B, Velenik V. Total neoadjuvant treatment of locally advanced rectal cancer with high risk factors in Slovenia. Radiol Oncol. 2019 Oct 25;53(4):465-472. doi: 10.2478/raon-2019-0046. |
| 31150315 | Background | Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, Kuhnt T, Staib L, Brunner T, Grosu AL, Schmiegel W, Jacobasch L, Weitz J, Folprecht G, Schlenska-Lange A, Flentje M, Germer CT, Grutzmann R, Schwarzbach M, Paolucci V, Bechstein WO, Friede T, Ghadimi M, Hofheinz RD, Rodel C; German Rectal Cancer Study Group. Randomized Phase II Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019 Dec 1;37(34):3212-3222. doi: 10.1200/JCO.19.00308. Epub 2019 May 31. |
| 30210040 | Background | Golo D, But-Hadzic J, Anderluh F, Brecelj E, Edhemovic I, Jeromen A, Omejc M, Oblak I, Secerov-Ermenc A, Velenik V. Induction chemotherapy, chemoradiotherapy and consolidation chemotherapy in preoperative treatment of rectal cancer - long-term results of phase II OIGIT-01 Trial. Radiol Oncol. 2018 Sep 11;52(3):267-274. doi: 10.2478/raon-2018-0028. |
| 27727065 | Background | But-Hadzic J, Anderluh F, Brecelj E, Edhemovic I, Secerov-Ermenc A, Hudej R, Jeromen A, Kozelj M, Krebs B, Oblak I, Omejc M, Vogrin A, Velenik V. Acute Toxicity and Tumor Response in Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy With Shortening of the Overall Treatment Time Using Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost: A Phase 2 Trial. Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):1003-1010. doi: 10.1016/j.ijrobp.2016.08.031. Epub 2016 Aug 31. |
| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
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