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The purpose of this study is to determine whether 4 cycles of neoadjuvant CapOx chemotherapy is more effective than the upfront surgery in patients with intermediate risk CRM"-" mid and upper rectal cancer.
This trial aims to investigate the efficacy of neoadjuvant chemotherapy compared to upfront surgery in intermediate risk rectal cancer patients. This is a prospective multicenter open-label randomized phase III clinical trial. Patients will be randomized using an online randomization system to receive either 4 cycles of neoadjuvant CapOx (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 per os bid days 1-14) chemotherapy and surgery or surgery alone. A stratification will be performed based on N stage, tumor location in the middle or upper rectum and clinical center. Patients with cT3-4aN1-2M0, T4aN0M0 cancer in the upper rectum and сТ2-Т3bN1M0 (based on preoperative MRI) cancer in the middle rectum are included. All patients are potential candidates for adjuvant chemotherapy, according to preoperative staging. Chemoradiotherapy (50 Gy with concomitant capecitabine 825 mg/m2 per os bid on radiation days) will be performed for patients with tumor progression after neoadjuvant chemotherapy. The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage in both treatment arms, according to actual treatment guidelines. The target accrual is 280 patients in each treatment arm (including 10% potential data loss) based on potential benefit of 10% 3-yr disease-free survival (75% vs 85%), α=0,05, power 80% in the experimental arm. An interim analysis is planned after 50% of the patients will reach a 3-year followup. Pelvic Magnetic Resonance Imaging (MRI) is performed in all patients for staging before and after neoadjuvant chemotherapy and before surgery. Pelvic MRI isbject to central review. Conduction of this study and data collection are controlled by a local institutional board.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 4xCapOx | Experimental | Patients will receive 4 cycles of neoadjuvant CapOx chemotherapy (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 bid per os days 1-14 every 3 weeks). In case of partial response or stable disease (based on pelvic MRI) patients proceed to surgery. In case of disease progression patients receive 50 Gy pelvic chemoradiotherapy with capecitabine 825 mg/m2 bid per os on radiation days and then surgery. The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage |
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| Surgery | Active Comparator | Patients will receive standard surgery for rectal cancer with partial or total mesorectal excision (based on exact tumor location and surgeons discretion). The decision to proceed with adjuvant chemotherapy postoperatively will be based on pTNM stage |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Capecitabine | Drug | 2000 mg/m2, bid, per os, days 1-14, 4 cycles |
|
| Measure | Description | Time Frame |
|---|---|---|
| 3-year disease-free survival | 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Adjuvant chemotherapy compliance | Proportion of patients who receive a complete course of adjuvant chemotherapy | 6 months |
| Acute chemotherapy toxicity | Toxicity measured according to NCI-CTCAE v.5.0 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Zaman Z Mamedli, PhD | N.N.Blokhin Russian Cancer Research Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| N.N.Blokhin Russian Cancer Research Center | Moscow | 115478 | Russia |
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| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D000069287 | Capecitabine |
| D000077150 | Oxaliplatin |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
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| Oxaliplatin | Drug | 130 mg/m2 iv day 1, 4 cycles |
|
| Capecitabine | Drug | 825 mg/m2, bid, per os, only on days of radiation (Monday through Friday) |
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| Radiotherapy | Radiation | Pelvic radiotherapy dose: 44 Gy on regional nodes, 50 Gy on primary tumor |
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| Rectal cancer surgery | Procedure | Laparoscopic or open partial or total mesorectal excision (based on exact tumor location and surgeons discretion) |
|
| 14 weeks |
| pathologic complete response rate (pCR) | 1 month |
| local recurrence rate | 3 years |
| 3-year overall survival | 3 years |
| Operative morbidity | Morbidity measured according to Clavien-Dindo classification | 30 days |
| Neoadjuvant chemotherapy disease progression rate | Proportion of patients with disease progression during neoadjuvant chemotherapy | 14 weeks |
| Preoperative tumor-associated complications rate | The rate of tumor-associated complications (bowel obastruction, bleeding etc) during neoadjuvant chemotherapy | 14 weeks |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D013812 | Therapeutics |