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Prospective Phase II Study of Preoperative Radiotherapy and
Oral Capecitabine followed by Total Mesorectal Exicision (TME)
in Locally Advanced Rectal Cancer
JH Kim M.D.1, J Park M.D.1, EK Choi M.D.1, SD Ahn M.D.1
S Lee M.D.1, SS Shin M.D.1, JC Kim M.D.2, CS You M.D.2
HC Kim M.D.2, TW Kim M.D.3, HM Chang M.D.3, MH Ryu M.D.3
Department of 1Radiation Oncology, 2Surgery, 3Internal medicine
Asan Medical Center, College of Medicine, University of Ulsan
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OBJECTIVES
To evaluate the tumor response, sphincter preservation
effect and acute toxicity of preoperative chemoradiation
therapy using oral capecitabine for locally advanced
rectal cancer
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MATERIALS AND METHODS
• Prospective phase II trials
• January 2002 – February 2004
• Locally advanced rectal adenocarcinoma
• Preoperative radiotherapy and oral capecitabine
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INCLUSION CRITERIA
• Histologically proven rectal adenocarcinoma
• Locally advanced rectal cancer in clinical evaluation
• Tumor distal border located within 10 cm from AV.
• ECOG performance score 0 – 2
• Adequate hematologic, renal, hepatic function
• Approved informed consent
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PRETREATMENT EVALUATION
• History taking and physical examination
• CBC, serum chemistry, CEA
• Sigmoidoscopy or colonoscopy with biopsy
• Endorectal (or transrectal) ultrasound
• Abdominal pelvic CT
• Chest X ray
• Chest CT (CEA > 20ng/ml) , bone scan (CEA > 40ng/ml)
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TREATMENT SCHEME( Chemotherapy )
• Preoperative
- 1,650 mg/m2/day, whole period of radiotherapy
- Given orally, divided into two doses
• Postoperative
- 2,500 mg/m2/day (D1-14, every 3 weeks) x 4
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• 6, 15 MV photon
• Multiple field technique (3 or 4 portals)
• Whole pelvis 46 Gy / 23 Fr. with tumor boost 4 Gy
• 5 days / week
TREATMENT SCHEME( Radiotherapy )
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TREATMENT SCHEME
#1 #2 #3 #4CT
RTSURGERY
Capecitabine1,650 mg/m2/day
50 Gy / 25 Fr.
Capecitabine2,500 mg/m2/day
0 4 8 12 16 20 24
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PATIENT CHARACTERISTICS ( I )
Characteristics No. (%)
Patient number 95
Age (years) Median 55 Range 31 – 75
Sex M 68 (72) F 27 (28)
Performance status 1 95 (100) (ECOG)
Histologic Diff. W/D 21 (22) M/D 58 (61)
P/D 5 (5) Other 11 (12)
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PATIENT CHARACTERISTICS ( II )
Characteristics No. (%)
Distance from AV (cm) Median 5 Range 0 - 10
Mobility Mobile 15 (16)
Tethered 44 (46) Fixed 31 (33) Unpalpable 5 (5)
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Clinical stage * No. (%)
T3N0 13 (14)
T3N1-2 56 (59)
T4N0 4 (4)
T4N1-2 22 (23)
Total 95 (100)
PATIENT CHARACTERISTICS ( III )
* Based on EUS and CT evaluation
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Modality No. (%)
Planned radiation dose
Complete 92 (97)
Incomplete 3 (3)
Planned chemotherapy dose
Complete 92 (97)
Incomplete 3 (3)
RESULTS: ComplianceRESULTS
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Extent of resection No. (%)
Microscopically complete 92 (98)
Microscopically incomplete 2 (2)
Macroscopically incomplete 1 (1)
Total* (%) 94 (100)
RESULTS: Extent of resection
RESULTS
* One patient did not have surgery due to multiple metastasis.
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RESULTS: Pathologic response I
pT
T stage pCR pT1 pT2 pT3 pT4
cT3 (n=68) 10 2 19 37 -
cT4 (n=26) 2 1 5 15 3
Total* (%) 12 (13) 3 (3) 24 (26) 52 (55) 3 (3)
RESULTS
- T down-stage: 54/94 (57%)* One patient did not have surgery due to multiple metastasis.
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pN
N stage pN0 pN1-2
cN0 (n=17) 11 6
cN1-2 (n=77) 53 24
Total* (%) 64 (68) 30 (32)
- N down-stage: 53/77 (69%)
RESULTS: Pathologic response II
RESULTS
* One patient did not have surgery due to multiple metastasis.
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T level down-stage
N level down-stage
Complete response
Overall down-stage
69 % (53/77)
76 % (71/94)
100 %
12 % (11/94)
57 % (54/94)
50 %
RESULTSRESULTS: Pathologic response III
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RESULTS: Sphincter preservation
RESULTS
Tumor distance from anal verge (cm)
Op. 0 – 5 6 – 10
LAR 40* 37
APR 14 3
Total 54 40 * Sphincter preservation rate (AV ≤ 5 cm) : 74% (40/54)Elongation of distal tumor margin: 0.8 ± 1.3 cm (mean ± SD; 0 - 5.5 cm)
Safe sphincter preservation rate: 37% (20/54)
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RESULTS: Acute toxicity (Hematologic)
RESULTS
Grade*
1 2 3 4
Leucopenia 41 (43%) 19 (20%) 1 (1%) -
Neutropenia 27 (28%) 5 (5%) 1 (1%) -
Anemia 46 (48%) 7 (7%) - -
Thrombocytopenia 1 (1%) - - -
Toxicity
*NCI CTC V2.0
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RESULTS: Acute toxicity (Nonhematologic)
RESULTS
Grade*
1 2 3 4
Proctitis 33 (35%) 7 (7%) - -
Diarrhea 3 (3%) 3 (3%) 3 (3%) -
Hand-foot syndrome 9 (10%) 3 (3%) - -
Radiation dermatitis 1 (1%) 14 (15%) - -
Stomatitis 5 (5%) - - -
Nause 17 (18%) 2 (2%) - -
Vomiting 3 (3%) 1 (1%) - -
Weight loss 1 (1%) - - -
Toxicity
*NCI CTC V2.0
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PERIOPERATIVE COMPLICATIONS
Complication * No. (%)
Mechanical ileus 1 (1)
Delayed wound healing 2 (2)
Wound infection 1 (1)
Wound dehiscence 2 (2)
Perianal abscess 1 (1)
Anastomotic leak 1 (1)
Total 8 (9) * Within 60 days from surgery
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Results of Preoperative Chemoradiation with Capecitabine
Authors No. No. Staging RT dose Drug* T stage N stage Overall stage Cinical pCR†
T4 workup down down down response
Kim 45 4 EUS/CT 50.4 Gy XL 63% 90% 84% - 31%(2002) / 28 Fr. (24/38) (26/29) (32/38) (12/38)
Kocakova 34 NR‡ EUS 50.4 Gy X 100% 100% 100% - 21%(2003) / 28 Fr. (7/34)
Shi 31 1 - 52.5 Gy X - - 71% - 18%(2004) / 30 Fr. (20/28) (5/28)
Dunst 58 50% - 55.8 Gy X 74% - - 61% 4%(2004) / 31 Fr. (37/50) (30/49) (2/50)
Wong 18 0 EUS/CT 50.4 Gy X 28% 86% 50% - 17%(2004) /MRI / 28 Fr. (5/18) (6/7) (9/18) (3/18)
De Paoli 53 13% - 50.4 Gy X - - 57% 58% 24%(2004) / 28 Fr. (29/51) (31/53) (12/51)
Dupois 51 1 EUS/CT 45 Gy X 59% - - - 24%
(2004) /MRI / 25 Fr.
Current 95 26 EUS/CT 50 Gy X 57% 69% 76% - 12%trial / 25 Fr. (54/94) (53/77) (71/94) - (11/94)
*X=capecitabine, L=leucovorin, †pCR=pathologic complete remission rate, ‡Not reported
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CONCLUSIONS
1. Preoperative chemoradiation with oral capecitabine and
conventionally fractionated radiotherapy achieved encoura
ging rates of tumor downstaging, enabling more sphincter
preservation, and reducing multivisceral resection with low
acute toxicity in this trial.
2. This combined modality was safe, effective, and convenien
t treatment for locally advanced rectal cancer