1. 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 1 Radiation Oncology, 2 Surgery, 3 Internal medicine Asan Medical Center, College of Medicine, University of Ulsan

2. OBJECTIVES To evaluate the tumor response, sphincter preservation effect and acute toxicity of preoperative chemoradiation therapy using oral capecitabine for locally advanced rectal cancer

3. MATERIALS AND METHODS Prospective phase II trials January 2002 – February 2004 Locally advanced rectal adenocarcinoma Preoperative radiotherapy and oral capecitabine

4. 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

5. 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)

6. TREATMENT SCHEME ( Chemotherapy ) Preoperative - 1,650 mg/m 2 /day, whole period of radiotherapy - Given orally, divided into two doses Postoperative - 2,500 mg/m 2 /day (D1-14, every 3 weeks) x 4

7. 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 )

8. TREATMENT SCHEME #1#2#3#4 CT RT SURGERYSURGERY Capecitabine 1,650 mg/m 2 /day 50 Gy / 25 Fr. Capecitabine 2,500 mg/m 2 /day 0 4 8 12 162024

9. 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)

10. 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)

11. Clinical stage * No. (%) T3N013(14) T3N1-256(59) T4N0 4(4) T4N1-222(23) Total 95(100) PATIENT CHARACTERISTICS ( III ) * Based on EUS and CT evaluation

12. Modality No. (%) Planned radiation dose Complete 92(97) Incomplete 3(3) Planned chemotherapy dose Complete 92(97) Incomplete 3(3) RESULTS : Compliance RESULTS

13. Extent of resection No. (%) Microscopically complete92(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.

14. RESULTS : Pathologic response I pT T stage pCRpT1pT2pT3pT4 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.

15. pN N stage pN0 pN1-2 cN0 (n=17) 11 6 cN1-2 (n=77) 5324 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.

16. 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 % RESULTS RESULTS : Pathologic response III

17. RESULTS : Sphincter preservation RESULTS Tumor distance from anal verge (cm) Op. 0 – 56 – 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)

18. RESULTS : Acute toxicity (Hematologic) RESULTS Grade* 1 2 34 Leucopenia41 (43%)19 (20%) 1 (1%)- Neutropenia27 (28%) 5 (5%) 1 (1%)- Anemia46 (48%) 7 (7%) -- Thrombocytopenia 1 (1%) - -- Toxicity *NCI CTC V2.0

19. RESULTS : Acute toxicity (Nonhematologic) RESULTS Grade* 1 2 34 Proctitis33 (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%) - -- Nause17 (18%) 2 (2%) - - Vomiting 3 (3%) 1 (1%) - - Weight loss 1 (1%) - - - Toxicity *NCI CTC V2.0

20. PERIOPERATIVE COMPLICATIONS Complication * No. (%) Mechanical ileus1 (1) Delayed wound healing2 (2) Wound infection1 (1) Wound dehiscence2 (2) Perianal abscess1 (1) Anastomotic leak1 (1) Total8 (9) * Within 60 days from surgery

21. Results of Preoperative Chemoradiation with Capecitabine AuthorsNo. No.StagingRT doseDrug*T stageN stageOverall stage Cinical pCR † T4workup down down downresponse Kim 45 4EUS/CT50.4 Gy XL 63% 90% 84% - 31% (2002) / 28 Fr. (24/38) (26/29) (32/38)(12/38) Kocakova34 NR ‡ EUS50.4 Gy X 100% 100% 100% - 21% (2003) / 28 Fr. (7/34) Shi31 1 -52.5 Gy X - - 71% - 18% (2004) / 30 Fr. (20/28) (5/28) Dunst58 50% -55.8 Gy X 74% - - 61% 4% (2004) / 31 Fr. (37/50) (30/49) (2/50) Wong18 0EUS/CT50.4 Gy X 28% 86% 50% - 17% (2004) /MRI / 28 Fr. (5/18) (6/7) (9/18) (3/18) De Paoli53 13% -50.4 Gy X - - 57% 58% 24% (2004) / 28 Fr. (29/51) (31/53) (12/51) Dupois51 1EUS/CT 45 Gy X 59% - - - 24% (2004) /MRI / 25 Fr. Current 95 26EUS/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

22. CONCLUSIONS 1.Preoperative chemoradiation with oral capecitabine and conventionally fractionated radiotherapy achieved encouraging 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 convenient treatment for locally advanced rectal cancer