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Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and 5-FU / leucovorin (FOLFOX 6)

5-FU: continuous infusion via portable pump during all RT (approximately 33 days)

5-FU

Oxaliplatin: 50mg/m2 weekly dosing during RT (Day 1)

Folinic Acid (Leucovorin): 400 mg/m2; 2-hour IV infusion simultaneously with oxaliplatin

leucovorin

mesorectal excision

Peter Kozuch, MD

RATIONALE: 5FU based neoadjuvant chemoradiation (nCRT) is the standard of care for Stage II/III rectal cancer. Pathologic complete response (pCR) and downstaging have been associated with improved outcomes. The addition of oxaliplatin (OXA) to neoadjuvant therapy may reduce distant disease recurrence. Adjuvant treatment with OXA for rectal cancer has been motivated by benefits demonstrated in stage III colon cancer.

Objective: To determine the feasibility, toxicity, and efficacy of preoperative OXA/5FU and RT followed by total mesorectal excision (TME) and adjuvant

PURPOSE: This phase II trial is studying the side effects and how well giving neo-adjuvant combination chemotherapy with radiation works in treating patients undergoing surgery for rectal cancer.

OBJECTIVES:

Primary

* To assess the complete pathologic response rate in patients with rectal cancer treated with radiation, modified neoadjuvant FOLFOX 6 chemotherapy followed by total mesorectal excision and adjuvant modified FOLFOX 6 chemotherapy.

Secondary

* To observe the overall pathologic response rate in these patients.
* To correlate pathologic staging with preoperative ultrasound and pelvic MRI staging.
* To assess toxic side effects of these regimens in these patients.
* To assess patterns of disease relapse, disease-free survival outcomes, and overall survival outcomes of these patients.

OUTLINE:

Patients with stage II/III rectal cancer were treated with OXA 60mg/m2 weekly continuous infusion 5FU of 225 mg/m2/d d1-5 with pelvic RT of 1.8Gy/d for 28 doses. Adjuvant therapy consisted of 6 cycles of biweekly FOLFOX6.

Surgery: Patients undergo total mesorectal excision by anterior resection or an abdominal perineal resection within 4 weeks after completion of neoadjuvant therapy.

Adjuvant therapy: Within 4 weeks after surgery, patients receive modified FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium IV over 2 hours on day 1 and continuous fluorouracil IV over 46 hours on days 1-2. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life assessment questionnaires at baseline and at each follow-up visit.

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and annually thereafter.

Neo-adjuvant Chemoradiation With Oxaliplatin/5-FU in Rectal Cancer

A Phase II Open-labeled, Prospective Study to Determine the Efficacy of Preoperative Chemoradiation With Oxaliplatin/5-FU in Locally Advanced Rectal Cancer Followed by Total Mesorectal Excision and FOLFOX6

Pathologic Response and Complete Response to preoperative therapy will be determined at the time of surgical resection. All grossly visible areas of ulceration and/or induration with be measured and submitted for histological evaluation.

The unit of measure is the tumor response rate to preoperative chemoradiation.

Pathologic complete response (pCR) is defined as no evidence of invasive tumor cells on pathologic examination of the primary rectal cancer.

Tumor regression grade (TRG) will be quantitated into five grades:

TRG 1 (complete regression) -absence of residual cancer and fibrosis extending from the site of original tumor through the layers of the rectal wall.

TRG 2 characterized by the presence of rare residual cancer cells scattered through the fibrosis.

TRG 3 characterized by an increase in the number of residual cancer cells, but fibrosis still predominant.

TRG 4 -residual cancer outgrowing fibrosis. TRG 5 characterized by absence of regressive changes.

Toxicity was assessed weekly during neoadjuvant chemotherapy and radiation therapy, bi-weekly during adjuvant FOLFOX therapy.

Complete resectability rates assessed by circumferential margin.

subjects were followed for median of 22 months post-surgery

Thin-section high resolution pelvic MRI was used to image the tumor prior to chemoradiation and repeated prior to surgery, and then compared to post-treatment pathological stage.

Beth Israel Medical Center

Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and FOLFOX 6

Chemoradiation,Surgery, Chemotherapy

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr Peter Kozuch

Pathologic Response and Complete Response

Preoperative Chemoradiation with oxaliplatin/5-FU followed by mesorectal excision and FOLFOX 6:

Preoperative therapy: Oxaliplatin 60 mg/m2 weekly dosing during radiation with continuous infusion 5-FU 225 mg/m2/d Monday through Friday for a total of 96 hours per week each week of radiation (approximately 6-7 weeks). Radiation dose will be 50-54Gy with possible intraoperative (IORT) radiation (10-12Gy).

Surgery: Total Mesorectal Excision

Postoperative therapy: FOLFOX6 every 2 weeks for 6 cycles (3 months)

According to the citation J Clin Oncol 28,2010 (suppl; abstract e14128): acute grade 3-4 toxicities occurred in 16 patients, mainly hypersensitivity reactions and OXA associated peripheral neuropathy.

Treatment Toxicity

Out of the 27 patients enrolled, a total 23 underwent TME.

Complete Resectability Rates

Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for local regional control.

Local Regional Control

Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for disease-free survival.

Disease-free Survival

Overall Survival

Out of the 27 patients enrolled, a total 23 underwent TME and were assessed for patterns of disease failure.

Patterns of Disease Failure, Including Local Recurrence and Distant Metastasis Assessed by CT Scan

Out of the 27 patients enrolled, a total 23 underwent TME. These 23 patients were included for comparison of preoperative stage and post-treatment pathologic stage.

Number of Participants With Comparison of Preoperative Stage With Post-treatment Pathologic Stage

Oxaliplatin/5-FU Followed by Mesorectal Excision and FOLFOX 6

Overall Study

Carcinoma

Capecitabine

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

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

2000 mg/m2, bid, per os, days 1-14, 4 cycles

825 mg/m2, bid, per os, only on days of radiation (Monday through Friday)

Pelvic radiotherapy dose: 44 Gy on regional nodes, 50 Gy on primary tumor

Radiotherapy

Laparoscopic or open partial or total mesorectal excision (based on exact tumor location and surgeons discretion)

Rectal cancer surgery

Zaman Z Mamedli, PhD

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.

Neoadjuvant Chemotherapy in Patients With Intermediate Risk Upper and Mid Rectal Cancer

A Multicenter Prospective Phase III Clinical Trial of Neoadjuvant CapOx Chemotherapy in Patients With Intermediate Risk Middle and Upper Rectal Cancer

Proportion of patients who receive a complete course of adjuvant chemotherapy

Toxicity measured according to NCI-CTCAE v.5.0

Morbidity measured according to Clavien-Dindo classification

Proportion of patients with disease progression during neoadjuvant chemotherapy

The rate of tumor-associated complications (bowel obastruction, bleeding etc) during neoadjuvant chemotherapy

Blokhin's Russian Cancer Research Center

Principal Investigator, Consultant surgeon

Bevacizumab

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

5 mg/kg intravenously every 2 weeks, 4 cycles

bevacizumab [Avastin]

capecitabine [Xeloda]

Radiation therapy

6-8 weeks after completion of neoadjuvant treatment

Mesorectal excision

Post-surgery adjuvant treatment at the discretion of the investigator: 5 mg/kg iv every 2 weeks for at least 6 months

Post-surgery adjuvant therapy: bolus of 400mg/m2 iv plus iv infusion of 600 mg/m2 on Days 1 and 2 of each 2-week cycle for 6 months

5-fluorouracil

Post-surgery adjuvant treatment: 100 mg/m2 iv on Days 1 and 2 of each 2-week cycle for 6 months

Clinical Trials

This open-label study will assess the efficacy and safety of Avastin (bevacizumab) plus Xeloda (capecitabine) in combination with standard technique radiotherapy of the pelvic region in the neo-adjuvant setting in patients with locally advanced primary rectal cancer. Patients will receive 4 courses of Avastin at a dose of 5 mg/kg intravenously (iv) every 2 weeks and for 38 days Xeloda at dose of 825 mg/kg twice daily orally, plus radiation therapy. After surgery, adjuvant treatment with 5-fluorouracil/leucovorin and, at the discretion of the investigator, with Avastin 5 mg/kg iv every 2 weeks for at least 6 months will be given.

A Study of Avastin (Bevacizumab) Plus Xeloda (Capecitabine) in Patients With Locally Advanced Rectal Cancer.

An Open-label Study to Assess the Effect of Combination Treatment With Avastin and Xeloda, Plus Pre-operative Standard Radiotherapy, on Response Rate in Patients With Locally Advanced Rectal Cancer.

pCR was defined as the absence of viable tumor cells, as determined by standard histologic procedure, in the tumor specimen (including regional lymph nodes) obtained at surgery. In order to minimize evaluation bias, tumor specimens were analyzed by both a central and local pathologist. The number of participants with pathological tumor stage 0 (pT0) and regional lymph nodes stage 0 (pN0) at surgery was determined. pCR was defined as the number of participants with pT0 and pN0 at surgery divided by the total number of participants with pathological tumor stage data collected.

The frequencies of clinical tumor stage T (0, 1, 2, 3, 4, or X), regional lymph nodes stage N (0, 1, 2, 3, or 4), and distant metastasis clinical stage M (0, 1, or X) at baseline and at the end of NAT were assessed. The frequencies of pathological tumor stage T and regional lymph nodes stage N at surgery were evaluated. The clinical tumor and lymph node status was assessed by clinical examination, endosonography, and/or rectosigmoidoscopy, and pelvic and abdomen computerized tomography (CT) scan or magnetic resonance imaging (MRI). Response to treatment had to be assessed within 6 weeks after end of treatment by using the same techniques performed at baseline.

Percentage of participants with CR was evaluated as the proportion of participants with complete response for the target and non-target lesions, separately, at the end of NAT according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as disappearance of all target lesions or all non-target lesions and normalization of tumor marker levels.

Percentage of participants with an overall response of CR was evaluated as the proportion of participants with CR for the target and non-target lesions plus absence of new lesions at the end of NAT according to RECIST. CR was defined as disappearance of all target lesions, all non-target lesions, and normalization of tumor marker levels.

The percentage of participants with new lesions located at the primary tumor site were evaluated at the end of NAT.

The percentage of participants with local and/or regional relapse during follow-up. New lesions located at rectum or at colon or at lymph node detected at the end of NAT were evaluated as local and/or regional relapse.

DFS was defined as the time from treatment start date to the date of first progression of disease or date of death due to any cause.

The time in months from date of start-of-treatment to the date of event defined as the first documented disease progression or death due to any cause. If a participant did not have an event, the time was censored at the date of last adequate tumor assessment. DFS was estimated using the Kaplan-Meier method.

OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive.

OS was defined as the time from the date of first day of treatment until death due to any cause or the last date the participant was known to be alive. OS was estimated using the Kaplan-Meier method.

TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer.

TTP was defined as the time from date of treatment start until first documented progression of disease or death due to underlying cancer. TTP was estimated using the Kaplan-Meier method.

Hoffmann-La Roche

All enrolled participants who received at least 1 dose of study medication were included in the safety population.

Participants received bevacizumab 5 mg/kg IV on Days -14, 1, 15, and 29 and capecitabine 825 mg/m\^2 PO BID from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gy administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m\^2 IV (over 2 hours) followed by 5-FU 400 mg/m\^2 IV bolus and then 5-FU 600 mg/m\^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.

Bv+Capecitabine/Bv+Leucovorin+5-FU

Intent to treat (ITT) population: all participants who were included in the trial by signing the informed consent and were assigned to a study patient number.

Medical Communications

ITT population; only participants who underwent surgery and had pathological tumor stage data were included in the analysis.

Percentage of Participants With Pathological Complete Response (pCR)

Baseline: T0, N0

End of NAT: T0, N0

Baseline: T1, N0

End of NAT: T1, N0

Baseline: T1, NX

End of NAT: T1, NX

Baseline: T2, N0

End of NAT: T2, N0

Baseline: T2, N1

End of NAT: T2, N1

Baseline: T2, NX

End of NAT: T2, NX

Baseline: T3, N0

End of NAT: T3, N0

Baseline: T3, N1

End of NAT: T3, N1

Baseline: T3, N2

End of NAT: T3, N2

Baseline: T3, NX

End of NAT: T3, NX

Baseline: T4, N0

End of NAT: T4, N0

Baseline: T4, N1

End of NAT: T4, N1

Baseline: T4, N2

End of NAT: T4, N2

Baseline: T4, N3

End of NAT: T4, N3

Baseline: TX, N0

End of NAT: TX, N0

Baseline: TX, N2

End of NAT: TX, N2

Baseline: M0

End of NAT: M0

Baseline: M1

End of NAT: M1

Baseline: MX

End of NAT: MX

Percentage of Participants by Primary Tumor (T), Regional Lymph Nodes (N), and Distant Metastasis (M) Clinical Stage at Baseline and at the End of Neo-Adjuvant Treatment (NAT)

Anterior resection

Abdomen-peritoneal amputation (Miles)

Other

Colostomy, temporary (n=32)

Colostomy, definitive (n=32)

No colostomy

ITT population; only participants who underwent surgery were included in the analysis. n (number) equals (=) number of participants assessed for the specified parameter (colostomy)

Percentage of Participants Undergoing Sphincter-Saving Surgery by Type of Procedure

CR of target lesion(s)

CR of non-target lesion(s)

Percentage of Participants With Complete Response (CR) at the End of Neoadjuvant Treatment

Percentage of Participants With an Overall Response of CR at the End of Neoadjuvant Treatment

Percentage of Participants With New Lesions at the Primary Tumor Site at the End of Neoadjuvant Treatment

No Relapse

1 Relapse

2 Relapses

ITT population; only participants who underwent radical surgery were included in the analysis

Percentage of Participants With Relapse During Follow-Up

Disease-Free Survival (DFS) - Percentage of Participants With an Event

DFS - Time to Event

Overall Survival (OS) - Percentage of Participants With an Event

OS - Time to Event

Time to Disease Progression (TTP) - Percentage of Participants With an Event

TTP - Time to Event

Participants received bevacizumab 5 milligrams per kilogram (mg/kg) intravenously (IV) on Days -14, 1, 15, and 29 and capecitabine 825 milligrams per square meter (mg/m\^2) orally (PO) twice daily (BID) from Days 1 to 38. Participants also received radiation therapy given at a daily fraction of 1.8 Gray (Gy) administered in 5 weekly fractions starting at Week 1 (through Week 6) for a maximum total dose of 45 Gy. Six to 8 weeks following all above treatments, participants received complete mesorectal excision surgery. After surgery, participants received bevacizumab 5 mg/kg IV on Day 1 and leucovorin 100 mg/m\^2 IV (over 2 hours) followed by 5-fluorouracil (5-FU) 400 mg/m\^2 IV bolus and then 5-FU 600 mg/m\^2 IV (over 22 hours) on Days 1 and 2 every 2 weeks for a maximum of 12 cycles.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Neo-adjuvant Chemoradiation With Oxaliplatin/5-FU in Rectal Cancer	NCT00831181	Colorectal Canc...	5-FU Oxaliplatin leucovorin mesorectal exci...	18 Years -	Beth Israel Medical Center
Neoadjuvant Chemotherapy in Patients With Intermediate Risk Upper and Mid Rectal Cancer	NCT04103697	Rectal Neoplasm... Rectum Carcinom... Rectal Cancer	Capecitabine Oxaliplatin Capecitabine Radiotherapy Rectal cancer s...	18 Years - 70 Years	Blokhin's Russian Cancer Research Center
A Study of Avastin (Bevacizumab) Plus Xeloda (Capecitabine) in Patients With Locally Advanced Rectal Cancer.	NCT01227707	Colorectal Canc...	bevacizumab [Av... capecitabine [X... Radiation thera... Mesorectal exci... bevacizumab [Av... 5-fluorouracil leucovorin	18 Years -	Hoffmann-La Roche
Neo-adjuvant Chemoradiation With Oxaliplatin/5-FU in Rectal Cancer	NCT00831181	Colorectal Canc...	5-FU Oxaliplatin leucovorin mesorectal exci...	18 Years -	Beth Israel Medical Center

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