Liver Metastases, Rectal Cancer
Conditions
Keywords
Rectal cancer, Liver metastases, Capecitabine, Oxaliplatin
Brief summary
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.
Detailed description
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.
Interventions
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.)
RADIATIONRadiotherapy
Preoperative radiotherapy, 5040 cGy with 28 fractions
Sponsors
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed adenocarcinoma of the rectum Tumor located within 12 cm from anal verge Clinical stage of T3-4 or N+ by rectal MRI ± endorectal ultrasound Age over 18 years No prior systemic treatment or radiation Adequate major organ functions Borderline resectability of primary rectal cancer Complete resectability of liver metastases (measurable by RECIST 1.1)
Exclusion criteria
* Unresectable liver metastases (6 or more metastatic lesions, major vessel invasion) * Extrahepatic metastasis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Surgery for Primary Tumor | 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 = 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 |
| Quality of Surgery for Liver Metastases | 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 = 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 |
| R0 Resection Rate of Both the Primary Tumor and Livermetastases | 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) | synchronous complete R0 resection rate, R0 = complete resection with grossly and microscopically negative margins of resection |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response Rate of Primary Tumor | 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) | 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). |
| Tumor Regression Grade (Primary Tumor) | 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) | 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 |
Countries
South Korea
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Induction XELOX-RT (Arm A) induction XELOX followed by XELOX-RT (arm A) | 18 |
| XELOX-RT Alone (Arm B) no induction XELOX, XELOX-RT alone (arm B) | 20 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Pregressive disease | 0 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Induction XELOX-RT (Arm A) | XELOX-RT Alone (Arm B) | Total |
|---|---|---|---|
| Age, Customized Age (years), median (range) | 60 years | 56 years | 58 years |
| Carcinoembryonic antigen (ug/ml), median (range) | 7.4 ng/ml | 6.9 ng/ml | 7.15 ng/ml |
| Clinical N Stage cN0 | 1 Participants | 0 Participants | 1 Participants |
| Clinical N Stage cN1 | 5 Participants | 5 Participants | 10 Participants |
| Clinical N Stage cN2 | 12 Participants | 15 Participants | 27 Participants |
| Clinical T Stage cT3 | 12 Participants | 16 Participants | 28 Participants |
| Clinical T Stage cT4 | 6 Participants | 4 Participants | 10 Participants |
| Distance of the primary tumor from the anal verge > 4 and ≤ 8 cm | 10 Participants | 7 Participants | 17 Participants |
| Distance of the primary tumor from the anal verge ≤ 4 cm | 6 Participants | 13 Participants | 19 Participants |
| Distance of the primary tumor from the anal verge > 8 cm | 2 Participants | 0 Participants | 2 Participants |
| Largest size of liver metastases (cm), median (range) | 1.8 cm | 2.4 cm | 2.1 cm |
| Number of liver metastases 1 metastases | 6 Participants | 7 Participants | 13 Participants |
| Number of liver metastases 2 metastases | 4 Participants | 5 Participants | 9 Participants |
| Number of liver metastases ≥3 metastases | 8 Participants | 8 Participants | 16 Participants |
| Number of liver metastases 1 | 6 Participants | 7 Participants | 13 Participants |
| Number of liver metastases 2 | 4 Participants | 5 Participants | 9 Participants |
| Number of liver metastases ≥3 | 8 Participants | 8 Participants | 16 Participants |
| Perfomance status (ECOG PS) 0 | 0 Participants | 5 Participants | 5 Participants |
| Perfomance status (ECOG PS) 1 | 18 Participants | 15 Participants | 33 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 34 Participants |
| Tumor differentiation Moderately differentiated | 13 Participants | 16 Participants | 29 Participants |
| Tumor differentiation Poorly differentiated/signet ring cell/mucinous | 0 Participants | 1 Participants | 1 Participants |
| Tumor differentiation Undetermined | 2 Participants | 0 Participants | 2 Participants |
| Tumor differentiation Well differentiated | 3 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 1 / 15 | 0 / 20 | 0 / 14 | 0 / 17 |
| other Total, other adverse events | 18 / 18 | 15 / 15 | 20 / 20 | 14 / 14 | 17 / 17 |
| serious Total, serious adverse events | 0 / 18 | 0 / 15 | 0 / 20 | 0 / 14 | 0 / 17 |
Outcome results
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
Time frame: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Induction XELOX-RT (Arm A) | Quality of Surgery for Liver Metastases | R0 | 11 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Liver Metastases | R1 | 1 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Liver Metastases | R0 with intraoperative Rdiofrequency ablation | 3 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Liver Metastases | R2 | 1 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Liver Metastases | Surgery not performed | 2 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Liver Metastases | R2 | 2 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Liver Metastases | Surgery not performed | 1 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Liver Metastases | R0 | 12 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Liver Metastases | R0 with intraoperative Rdiofrequency ablation | 2 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Liver Metastases | R1 | 3 Participants |
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
Time frame: 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 | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Induction XELOX-RT (Arm A) | Quality of Surgery for Primary Tumor | Surgery not performed | 2 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Primary Tumor | R0 | 15 Participants |
| Induction XELOX-RT (Arm A) | Quality of Surgery for Primary Tumor | R1 | 1 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Primary Tumor | Surgery not performed | 1 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Primary Tumor | R0 | 19 Participants |
| XELOX-RT Alone (Arm B) | Quality of Surgery for Primary Tumor | R1 | 0 Participants |
p-value: 0.71995% CI: [0.346, 6.501]t-test, 1 sided
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
Time frame: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Induction XELOX-RT (Arm A) | R0 Resection Rate of Both the Primary Tumor and Livermetastases | 77.8 percentage of patients |
| XELOX-RT Alone (Arm B) | R0 Resection Rate of Both the Primary Tumor and Livermetastases | 70.0 percentage of patients |
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).
Time frame: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Induction XELOX-RT (Arm A) | Pathologic Complete Response Rate of Primary Tumor | 11.1 percentage of participants |
| XELOX-RT Alone (Arm B) | Pathologic Complete Response Rate of Primary Tumor | 5.0 percentage of participants |
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
Time frame: 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)
Population: Tumor regression grade (primary tumor)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Induction XELOX-RT (Arm A) | Tumor Regression Grade (Primary Tumor) | Total regression | 2 Participants |
| Induction XELOX-RT (Arm A) | Tumor Regression Grade (Primary Tumor) | Moderate regression | 10 Participants |
| Induction XELOX-RT (Arm A) | Tumor Regression Grade (Primary Tumor) | Near total regression | 2 Participants |
| Induction XELOX-RT (Arm A) | Tumor Regression Grade (Primary Tumor) | Minimal regression | 2 Participants |
| Induction XELOX-RT (Arm A) | Tumor Regression Grade (Primary Tumor) | Surgery not performed | 2 Participants |
| XELOX-RT Alone (Arm B) | Tumor Regression Grade (Primary Tumor) | Minimal regression | 3 Participants |
| XELOX-RT Alone (Arm B) | Tumor Regression Grade (Primary Tumor) | Surgery not performed | 1 Participants |
| XELOX-RT Alone (Arm B) | Tumor Regression Grade (Primary Tumor) | Total regression | 1 Participants |
| XELOX-RT Alone (Arm B) | Tumor Regression Grade (Primary Tumor) | Near total regression | 4 Participants |
| XELOX-RT Alone (Arm B) | Tumor Regression Grade (Primary Tumor) | Moderate regression | 11 Participants |