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To investigate the feasibility of preoperative chemoradiation with oxaliplatin plus capecitabine, with or without prior induction chemotherapy in patients with locally advanced or marginally resectable rectal cancer with resectable synchronous liver metastases.
Preoperative chemoradiation is now an initial treatment of choice for locally advanced resectable rectal cancer, and 5-fluorouracil is the standard agent during chemoradiation. Capecitabine is an oral fluoropyrimidine which has been thought to be a replacement for intravenous 5-fluorouracil, and several trials have proved that preoperative chemoradiation with capecitabine was also effective in this setting.
Oxaliplatin, a newer platinum agent, plus fluoropyrimidines (either 5-fluorouracil or capecitabine) is one of the standard cytotoxic chemotherapeutic regimen for metastatic colorectal cancer, and it is also proved to be effective as neoadjuvant chemotherapy for patients with liver only metastasis from colorectal cancer.
Approximately 25% of patients with colorectal cancer have liver metastases initially at the time of diagnosis and there have been quite well established evidences for clear survival benefits from hepatic metastasectomy in these patients. Treatment for colorectal liver metastases should be planned with consideration of both systemic chemotherapy and local treatment modality (surgery or radiofrequency ablation) because long term survival would be expected after curative liver metastasectomy. As mentioned previously, neoadjuvant oxaliplatin plus fluoropyrimidines before hepatic metastasectomy improved disease-free survival, thus it is thought to be that better systemic controls would be achieved with perioperative oxaliplatin based chemotherapy.
In patients with locally advanced rectal cancer, preoperative chemoradiation with fluoropyrimidines improves local control but not systemic control. Recent randomized trials of preoperative chemoradiation with oxaliplatin plus fluoropyrimidines failed to show better local control rates than those with fluoropyrimidines alone. But it is too early to determine the non-superiority of preoperative chemoradiation with oxaliplatin plus fluoropyrimidines in terms of systemic control; long-term duration of follow-up is needed to determine the efficacy in terms of disease-free or overall survival and it is evident that oxaliplatin based chemotherapy is effective for systemic control in patients who will be candidate for liver metastasectomy.
Thus, the investigators planned a randomized phase II trial of preoperative chemoradiation with oxaliplatin plus capecitabine, with or without prior induction chemotherapy in patients with locally advanced or borderlinely resectable rectal cancer with resectable synchronous liver metastases.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| XELOX RT | Active Comparator | Concurrent XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy) |
|
| Induction XELOX | Active Comparator | Induction XELOX(Capecitabine, Oxaliplatin) followed by XELOX-RT (Capecitabine, Oxaliplatin, radiotherapy) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Capecitabine, Oxaliplatin | Drug | Induction chemotherapy - Induction XELOX (Capecitabine 1250 mg/m2 PO twice daily on D1-14 and oxaliplatin 130 mg/m2 on D1, every 3 weeks for 2 cycles) Preoperative chemoradiotherapy - XELOX RT (Capecitabine 825 mg/m2 PO twice daily during radiotherapy and oxaliplatin 50 mg/m2/day on weekly.) |
| Measure | Description | Time Frame |
|---|---|---|
| Quality of Surgery for Primary Tumor | R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
| Quality of Surgery for Liver Metastases | R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
| R0 Resection Rate of Both the Primary Tumor and Livermetastases | synchronous complete R0 resection rate, R0 = complete resection with grossly and microscopically negative margins of resection | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Pathologic Complete Response Rate of Primary Tumor | The pathologic stage (ypT or N) was recorded according to the International Union Against Cancer TNM system. Pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens, of the primary tumor (ypT0). | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tae Won Kim, Professor | Asan Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Asan Medical Center | Seoul | Songpa | 138736 | South Korea |
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Between March 2010 and May 2014, a total of 38 patients from 3 centers in Korea were enrolled. They underwent random assignment and 18 patients were assigned to arm A and 20 to arm B. The cutoff date for this report was March 15, 2015. Baseline characteristics of these patients are presented in Table 1, and they were well balanced between the 2 arms. The median number of LM was 2 and cT3N+ was the most common clinical disease stage in both arms.
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| ID | Title | Description |
|---|---|---|
| FG000 | Induction XELOX | Induction XELOX followed by XELOX-RT Capecitabine, Oxaliplatin: Induction chemotherapy - Capecitabine (1250 mg/m2 PO twice daily on D1-14 and oxaliplatin 130 mg/m2 on D1, every 3 weeks for 2 cycles) Preoperative chemoradiotherapy - Capecitabine 825 mg/m2 PO twice daily during radiotherapy and oxaliplatin 50 mg/m2/day on weekly. Radiotherapy: Preoperative radiotherapy, 5040 cGy with 28 fractions |
| FG001 | XELOX RT | Concurrent XELOX-RT Capecitabine, Oxaliplatin: Induction chemotherapy - Capecitabine (1250 mg/m2 PO twice daily on D1-14 and oxaliplatin 130 mg/m2 on D1, every 3 weeks for 2 cycles) Preoperative chemoradiotherapy - Capecitabine 825 mg/m2 PO twice daily during radiotherapy and oxaliplatin 50 mg/m2/day on weekly. Radiotherapy: Preoperative radiotherapy, 5040 cGy with 28 fractions |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Induction XELOX-RT (Arm A) | induction XELOX followed by XELOX-RT (arm A) |
| BG001 | XELOX-RT Alone (Arm B) | no induction XELOX, XELOX-RT alone (arm B) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Quality of Surgery for Primary Tumor | R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection | Posted | Count of Participants | Participants | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
|
Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks), followed by postoperative chemotherapy (XELOX, 18 weeks). Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks), followed by postoperative chemotherapy (XELOX, 18 weeks).
Adverse events were analyzed by treatment exposure. This included Induction Chemotherapy (only Arm A), Preoperative Chemoradiotherapy, and Postoperative Chemotherapy
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | During Induction XELOX (Arm A) | consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 2 cycles. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leucopenia | Blood and lymphatic system disorders | CTCAE (4.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Tae Won Kim | Asan Medical Center | +82-2-3010-3910 | twkimmd@amc.seoul.kr |
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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 |
|---|---|
| C519688 | XELOX |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D013812 | Therapeutics |
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|
| Radiotherapy | Radiation | Preoperative radiotherapy, 5040 cGy with 28 fractions |
|
| Tumor Regression Grade (Primary Tumor) | The regression of the primary tumor was quantified according to the 5-point tumor regression grade proposed by Dworak. Complete regression = No tumor cells ; Near complete regression = Very few tumor cells; Moderate regression = Dominantly fibrotic changes with few tumor cells or groups; Minimal regression = Dominant tumor mass with obvious fibrosis | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
| Pregressive disease |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Perfomance status (ECOG PS) | Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 0=Fully active, able to carry on all pre-disease performance without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; | Count of Participants | Participants |
|
| Distance of the primary tumor from the anal verge | Count of Participants | Participants |
|
| Tumor differentiation | Count of Participants | Participants |
|
| Clinical T Stage | Clinical staging determines how much cancer there is based on rectal magnetic resonance imaging (MRI). The T element designates the size and invasiveness of the primary tumor. cT3=Tumor invades through the muscularis propria into pericolorectal tissues; cT4=Tumor penetrates to the surface of the visceral peritoneum or directly invades or adheres to other organs or structures | Count of Participants | Participants |
|
| Clinical N Stage | Clinical staging determines how much cancer there is based on rectal magnetic resonance imaging (MRI). The N element designates the extent of regional lymph node involvement. cN0=No regional lymph node metastasis; cN1=One to Three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative; cN2=Four or more regional nodes are positive; | Count of Participants | Participants |
|
| Number of liver metastases | Count of Participants | Participants |
|
| Number of liver metastases | Count of Participants | Participants |
|
| Largest size of liver metastases (cm), median (range) | Median | Full Range | cm |
|
| Carcinoembryonic antigen (ug/ml), median (range) | Median | Full Range | ng/ml |
|
|
|
|
| Primary | Quality of Surgery for Liver Metastases | R0 = complete resection with grossly and microscopically negative margins of resection; R1 =grossly negative but microscopically positive margins of resection; R2 = grossly and microscopically positive margins of resection | Posted | Count of Participants | Participants | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
|
|
|
| Primary | R0 Resection Rate of Both the Primary Tumor and Livermetastases | synchronous complete R0 resection rate, R0 = complete resection with grossly and microscopically negative margins of resection | Posted | Number | 95% Confidence Interval | percentage of patients | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
|
|
|
| Secondary | Pathologic Complete Response Rate of Primary Tumor | The pathologic stage (ypT or N) was recorded according to the International Union Against Cancer TNM system. Pathologic complete response (ypCR) was defined as the absence of viable tumor cells in the surgical specimens, of the primary tumor (ypT0). | Posted | Number | 95% Confidence Interval | percentage of participants | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
|
|
|
| Secondary | Tumor Regression Grade (Primary Tumor) | The regression of the primary tumor was quantified according to the 5-point tumor regression grade proposed by Dworak. Complete regression = No tumor cells ; Near complete regression = Very few tumor cells; Moderate regression = Dominantly fibrotic changes with few tumor cells or groups; Minimal regression = Dominant tumor mass with obvious fibrosis | Tumor regression grade (primary tumor) | Posted | Count of Participants | Participants | Arm A = Induction chemotherapy (XELOX, 6 weeks) followed by chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks); Arm B = Chemoradiotherapy (XELOX plus radiotherapy) to surgery (6 weeks) |
|
|
|
| 0 |
| 18 |
| 0 |
| 18 |
| 18 |
| 18 |
| EG001 | During Preoperative Chemoradiotherapy With XELOX (Arm A) | consisted of radiation therapy with 45 Gy delivered in conventional fractionation (daily fractions of 1.8 Gy over a period of approximately 5 wk, excluding weekends) with or without additional 5.4 Gy delivery in daily fractions of 1.8 Gy over 3 days, oxaliplatin 50 mg/m2 weekly for 5 weeks, and capecitabine 825 mg/m2 twice daily on days 1 to 38 (during radiation therapy) | 1 | 15 | 0 | 15 | 15 | 15 |
| EG002 | During Preoperative Chemoradiotherapy With XELOX (Arm B) | consisted of radiation therapy with 45 Gy delivered in conventional fractionation (daily fractions of 1.8 Gy over a period of approximately 5 wk, excluding weekends) with or without additional 5.4 Gy delivery in daily fractions of 1.8 Gy over 3 days, oxaliplatin 50 mg/m2 weekly for 5 weeks, and capecitabine 825 mg/m2 twice daily on days 1 to 38 (during radiation therapy) | 0 | 20 | 0 | 20 | 20 | 20 |
| EG003 | During Postoperative XELOX (Arm A) | Surgery was planned with total mesorectal excision and simultaneous liver metastasectomy with or without addition of radiofrequency ablation within 6 weeks after completion of preoperative treatments. Postoperative chemotherapy (postoperative CapeOx) consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 6 cycles. | 0 | 14 | 0 | 14 | 14 | 14 |
| EG004 | During Posoperative XELOX (Arm B) | Surgery was planned with total mesorectal excision and simultaneous liver metastasectomy with or without addition of radiofrequency ablation within 6 weeks after completion of preoperative treatments. Postoperative chemotherapy (postoperative CapeOx) consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 6 cycles. | 0 | 17 | 0 | 17 | 17 | 17 |
| Neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Fatigue | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Sensory neuropathy | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Hand foot syndrome | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Anal pain | General disorders | CTCAE (3.0) | Systematic Assessment |
|
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| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| > 8 cm |
|
| Poorly differentiated/signet ring cell/mucinous |
|
| Undetermined |
|
| cN2 |
|
| ≥3 |
|
| R0 with intraoperative Rdiofrequency ablation |
|
| R1 |
|
| R2 |
|
| Near total regression |
|
| Moderate regression |
|
| Minimal regression |
|